Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind

 

Alzheimer’s disease and blood-brain barrier leakage

RadiologyAlzheimer’s disease is not a unitary condition but variable in causation at the individual level like all complex chronic disorders. Neuroinflammation, metabolic damage, vascular compromise, accumulation of noxious debris (amyloid β and tau), impairments in brain CSF and lymphatic drainage and other causes can all variously contribute to Alzheimer’s and other dementias. Now original research recently published in the journal Radiology demonstrates that leakiness of the blood-brain barrier (BBB) can permit an environment hostile to neuronal health that contributes to cognitive decline, Alzheimer’s and other dementias. The authors state:

“Evidence is increasing that impairment of the cerebral microvasculature is a contributing factor in the pathophysiology of Alzheimer disease (AD). However, the exact pathway remains unclear. Results of histologic evaluation and albumin sampling studies show that an increased permeability of the blood-brain barrier (BBB) is likely a key mechanism.”

An intact blood-brain barrier is essential for brain health

The BBB is a collection of cells and other structures in the cerebrovascular wall that when healthy permits only privileged access into the brain from the extra-cerebral blood compartment.

“It regulates the delivery of important nutrients to the brain through active and passive transport mechanisms and prevents neurotoxins from entering the brain. It also has a clearance function, meaning that it removes surplus substances from the brain. A well-functioning BBB is essential to keeping the brain tissue in a healthy condition. Results of previous studies suggest that deterioration of the BBB can cause an ill-conditioned environment for neuronal cells and other pathologic changes such as small-vessel abnormality, protein deposits, inflammation, and neuronal cell death. These changes eventually may lead to cognitive decline and dementia.”

Early Alzheimer’s shows abnormal BBB permeability

Blood-brain barrier degradation has earlier been demonstrated in advanced Alzheimer’s disease. Here the authors examined whether or not BBB leakage contributes to the early stages of disease.

“To investigate whether BBB leakage contributes to the early pathophysiology of AD, we hypothesized that patients with early forms of AD already show increased BBB permeability in comparison with age-matched control subjects. For this pilot study, we used a dedicated dynamic contrast-enhanced MR imaging acquisition protocol with dual-time resolution that separates the filling of the blood vessels from the leakage. We also investigated differences in local blood plasma volume fraction, and the relationship between BBB permeability and global cognition.”

The analyzed data for patients diagnosed with mild cognitive impairment (MCI) due to AD or patients or patients with early AD (a continuum of cognitive decline who had been referred by general practitioners because of memory concerns, in comparison with healthy controls. Individuals with dementia of vascular origin were excluded, as were those with major cardiovascular and neuropsychiatric disorders, Parkinson’s, MS, trauma, major structural abnormalities of the brain, and alcohol or drug abuse. They indeed demonstrated a marked distinction between their study subjects and controls:

“The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total GM (grey matter) and cortex but not in the WM, normal-appearing WM, deep GM, or WM hyperintensities…When adjustments were made for all covariates, the patients exhibited a significantly higher leakage volume in the WM and GM and also in the normal-appearing WM, deep GM, cortex, but not in WM hyperintensities…The median blood plasma volume was significantly lower in the patients than in the control subjects in all tissue classes.”

BBB leakage rate shown in early Alzheimer's

BBB leakage rate shown on the right, with some periventricular hot spots

BBB leakage in early Alzheimer’s is widespread

The leakage is not due to vascular abnormalities, and leakage volume was even more striking than rate:

The results of this study showed increased BBB leakage in patients with early AD. The leakage was globally distributed throughout the cerebrum and was associated with declined global cognitive performance. By using dynamic contrast-enhanced MR imaging with dual-time resolution, we found an increased BBB leakage rate in the GM of patients with early AD. By also showing very subtle BBB impairment in the WM, leakage volume proved to be even more sensitive to the differences in BBB leakage than was the leakage rate. Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class such as WM hyperintensities, normal-appearing WM, or cortex. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.”

Breakdown in tight junctions like the intestinal barrier

The intestinal barrier, critical for healthy immune system regulation, loses integrity with a breakdown of the tight cellular junctions. So too with the blood-brain barrier.

“The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis.”

Toxic accumulations in the brain and cognitive impairment

The authors have demonstrated that BBB leakage tracks cognitive impairment in early Alzheimer’s:

“We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.”

BBB and amyloid β

Clearance of amyloid β is also impaired:

“…amyloid β is actively transported across the BBB, whereas gadolinium leaks passively through the tight junctions. Previous work with positron emission tomographic data has shown that clearance of amyloid β is also impaired in patients with AD. An impaired clearance of amyloid β would mean that the BBB is impaired in different ways, contributing to the pathologic cascade leading to AD.”

Most importantly…

“Therefore, BBB leakage may help to provide a biomarker for early diagnosis, or at least a marker indicating vulnerability for the development of dementia. Successful prediction of dementia eventually might lead to optimized treatment, delay, or even prevention of the disease.”

Clinical note

Early diagnosis is key here, and for those of us without dynamic gadolinium contrast-enhanced MR imaging at hand I highly recommend the Blood Brain Barrier Permeability™ screen from Cyrex Labs (Array 20) which offers the clinician the ability to detect early changes in BBB permeability. Clinicians experienced in rehabilitation of the gut barrier will be familiar with resources to evaluate and remediate inflammation and other insults to the blood-brain barrier.

The authors conclude:

“…in this pilot study, MR imaging was used to show global, diffusely distributed BBB leakage in patients with early AD, which suggests that a compromised BBB is part of the early pathology of AD and might be part of a cascade of pathologic events that eventually lead to cognitive decline.”

  • “Patients with early Alzheimer disease have significantly more tissue characterized by blood-brain barrier leakage than do healthy control subjects, both in the normal-appearing white matter and in the gray matter.
  • Blood-brain barrier leakage in the gray matter correlates with lower scores on the Mini-Mental State Examination.”

Migraine, depression, Alzheimer’s and lipid metabolism

NeurologyMigraine, with its variety of symptoms associated with aberrant neuronal activation, is linked to abnormal metabolism of a class of bioactive lipids in an important study just published in the journal Neurology. Sphingolipids are involved in a variety of functions in mammalian systems including cell membrane formation, signaling, apoptosis, energy balance and inflammation. The authors set out to assess the levels of sphingolipids in circulation in women migraneurs between migraine attacks compared to control subjects. Their data show that altered sphingolipid metabolism clearly distinguished those with episodic migraine (EM) from controls:

Total ceramide (EM 6,502.9 ng/mL vs controls 10,518.5 ng/mL) and dihydroceramide (EM 39.3 ng/mL vs controls 63.1 ng/mL) levels were decreased in those with EM as compared with controls. Using multivariate logistic regression, each SD increase in total ceramide (odds ratio [OR] 0.07) and total dihydroceramide (OR 0.05) levels was associated with more than 92% reduced odds of migraine. Although crude sphingomyelin levels were not different in EM compared with controls, after adjustments, every SD increase in the sphingomyelin species C18:0 (OR 4.28) and C18:1 (OR 2.93) was associated with an increased odds of migraine. Recursive portioning models correctly classified 14 of 14 randomly selected participants as EM or control.”

Brain-liver axis and migraine

SphingolipidsThese interesting results shed light on a topic that deserves more attention: the role of the brain-liver axis in neuroinflammatory, neurodegenerative and neuropsychiatric disorders including migraine. This may be extended to include metabolism of lipids and other bioactive agents on a cellular level. The authors conclude in regard to sphingolipid metabolism and migraine:

“These results suggest that sphingolipid metabolism is altered in women with EM and that serum sphingolipid panels may have potential to differentiate EM presence or absence…This study provides Class III evidence that serum sphingolipid panels accurately distinguish women with migraine from women without migraine.”

Clinical note: for practitioners using medicines from the TCM (traditional Chinese medicine) and Ayurvedic systems the ‘brain-liver axis’ encompasses not just the visceral entity but consonant functions distributed throughout the organism.

Dementia, multiple sclerosis, obesity, and pain

Beyond migraine, a commentary on the study in Medscape Medical News states:

“The authors, led by B. Lee Peterlin, DO, from Johns Hopkins University School of Medicine, Baltimore, Maryland, note that neurologic disorders that are the result of severe deficiencies in enzymes that regulate sphingolipid metabolism have long been described (eg, Gaucher disease), and recent studies have suggested that even subtle changes of sphingolipid balance may be involved in dementia, multiple sclerosis, obesity, and pain…Now they also are reporting a study showing changes in sphingolipid levels in patients with migraine, implicating in particular two sphingolipid subtypes: ceramide and sphingomyelin…“Taken together, our findings suggest it is possible that migraine is a neurologic disorder of ‘minor’ sphingolipid dysmetabolism,” they conclude.”

Depression and anxiety

BBA - Molecular and Cell Biology of LipidsAlso in addition to migraine, a fascinating paper recently published in Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids reviews the function of neuronal membrane lipids including sphingolipids as a barrier and signaling medium in the brain and their role in depression and anxiety.

“Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membrane’s function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors.”

This opens the door to a class of treatment options…

“These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment.”

Alzheimer’s disease

Journal of Alzheimer's DiseaseA review in the Journal of Alzheimer’s Disease discusses the metabolism and the presence in biofluids of sphingolipids and other lipids in Alzheimer’s disease (AD):

“With the difficulties of studying the brain directly, it is hoped that identifying the effect of AD on the metabolite composition of biofluids will provide insights into underlying mechanisms of pathology…Sphingolipid, antioxidant, and glutamate metabolism were found to be strongly associated with AD and were selected for detailed investigation of their role in pathogenesis. In plasma, two ceramides increased and eight sphingomyelins decreased with AD, with total ceramides shown to increase in both serum and cerebrospinal fluid. In general antioxidants were shown to be depleted, with oxidative stress markers elevated in a range of biofluids in patients suggesting AD produces a pro-oxidative environment. Shifts in glutamate and glutamine and elevation of 4-hydroxy-2-nonenal suggests peroxidation of the astrocyte lipid bilayer resulting in reduced glutamate clearance from the synaptic cleft, suggesting a excitotoxicity component to AD pathology; however, due to inconsistencies in literature reports, reliable interpretation is difficult.”

In addition to defective clearance of amyloid beta, tau proteins and glutamate, altered sphingolipid metabolism emerges as a significant factor.

“The present review has shown that metabolite shifts in biofluids can provide valuable insights into potential pathological mechanisms in the brain, with sphingolipid, antioxidant, and glutamate metabolism being implicated in AD pathology.”

Sphingolipids in food

Journal of NutritionSphingolipids are in a variety of foods and, though not known to be an ‘essential’ nutrient, have functional effects as discussed in a paper published in the The Journal of Nutrition. The authors state:

“There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions…both complex sphingolipids and their digestion products (ceramides and sphingosines) are highly bioactive compounds that have profound effects on cell regulation. This article reviews the structures of sphingolipids, their occurrence in food, digestion and metabolism, biochemical functions and apparent roles in both the etiology and prevention of disease.”

Sphingolipids and cell regulationIn regard to their functional role:

“Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a “functional” constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds. “

The authors offer a table showing sphingolipid levels in various foods.

Systemic inflammation drives brain neurodegeneration

Frontiers in Cellular NeuroscienceIn a richly valuable paper published recently in Frontiers in Cellular Neuroscience the authors describe the ways in which systemic inflammation causes neurodegeneration in the brain associated with cognitive decline and a host of neuropsychiatric disorders. In the short term this manifests the anorexia, malaise, depression, and decreased physical activity known as sickness behavior (SB) that occurs with inflammation due to infection. Permanent cognitive and behavioral changes due to neurodegeneration occur when inflammation is chronic. Discerning and targeting the causes of inflammation offers opportunities for treatment.

Neuroimmune modulation

The nervous system senses inflammation directly and can exert control through the vagus nerve:

“The efferent axis of neuroimmune control is better understood after the cholinergic anti-inflammatory pathway (CAP), a cholinergic reflex system that regulates inflammation via the vagus nerve that stimulates the splenic nerve to release noradrenaline. Noradrenaline in turn stimulates a subset of acetylcholine (ACh)-producing splenic T-cells (CD4+CD44hiCD62Llo) to release ACh, which binds to α7 nicotinic receptors on the surface of macrophages, resulting in down-regulation of TNF by blocking the nuclear translocation of nuclear factor kappa B (NF-κB). Thus far, this is a unique scenario in which an immune cell acts as interneuron in a reflex system. Electrical as well as chemical stimulation of the CAP have been shown to decrease the inflammatory burden and increase survival of experimental sepsis.”

The a cholinergic response expressed through the vagus nerve can wind down inflammation and protect against neurodegeneration.

Sickness behavior

Transient inflammation, such as associated with a cold or flu, produces behavioral symptoms of the same character as those which persist with the chronic systemic inflammation that can drive neurodegeneration.

“The acute effects of systemic inflammation upon cognition and behavior are not limited to the elderly or the critically ill. As we have witnessed in ourselves and those near us, even a minor and self-limited common cold induces a transient syndrome known as sickness behavior (SB) marked by fatigue, depression, lack of drive, malaise, sleep disturbances, decreased physical activity, and social interactions, as well as cognitive impairment. Healthy volunteers develop anxiety, depression, and memory impairment in response to a low dose of lipopolysaccharide (LPS), and the development of such clinical scenario correlates with TNF secretion.”

And patients with chronic infections such as tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HVB), and hepatitis C virus (HCV) can have cognitive and behavioral problems due to the persistent inflammatory response.

“This supports the role of large loads of inflammatory cytokines in inducing and sustaining brain dysfunction. Experimentally, NADPH oxidative activity and nitric oxide synthase (iNOS) are induced in the brain shortly after systemic inflammation, potentially leading to NMDA-dependent neurotoxicity”

Sepsis and severe trauma

An overwhelming load of pathogens or severe trauma can unleash an immune inflammatory response that results in neurodegeneration.

“Under normal conditions, inflammation is a well-orchestrated response with constant fine-tuning. Once microorganisms have breached the skin and mucosal barriers, innate immunity is critical in preventing further invasion by launching inflammation. After the infection source has been cleared, the inflammatory response also plays an important role in tissue repair and functional healing. When the source of damage has been controlled, the same mechanisms that initiated and regulated inflammation will dampen the response. Large loads of pathogens, or infection by highly virulent pathogens, can trigger an en-masse systemic response that leads to sepsis and multiple organ failure…The nervous system is particularly vulnerable to damage in response to systemic inflammation.”

Brain milieu changes in response to systemic inflammation

Brain milieu changes in response to systemic inflammation

Inflammation-induced infiltration of immune cells and mediators into the brain leads to profound structural and functional changes. As a consequence, up to 81% of septic patients develop sepsis-associated delirium (SAD), with elderly patients being at particularly high risk. In the elderly, severe sepsis is sufficient to trigger new cognitive decline of sufficient importance as to profoundly interfere with quality of life…Neonatal sepsis is also marked by abnormalities of the white matter (66% of infants in one cohort), and white matter lesions correlate to poorer mental and psychomotor development at 2 years.

Moreover…

“…clearing the trigger of sepsis does not prevent the appearance of persistent brain damage…in a model of endotoxemia in aged rats, a single systemic injection of LPS induced brain inflammation that lasted for at least 30 days…This suggests that even transient bouts of systemic inflammation of only limited significance can cause sustained brain damage.”

Traumatic inflammation also promotes neurodegeneration:

“Severe trauma, as well as surgery can lead to large loads of endogenous pro-inflammatory molecules (damage-associated molecular patterns (DAMPs) being released. A few DAMPs have been shown to induce brain dysfunction in vivo. Of those, TNF and IL-1 can mediate long-standing cognitive and behavioral changes and, in experimental settings, interfering with the effect of TNF reduces the effect of trauma in the formation of contextual memory.”

In this context antioxidants can have neuroprotective effects.

“Experimentally, preemptive administration of the free radical scavenger endarvone before sepsis induction resulted in reduced neuronal damage and blood–brain barrier (BBB) permeability. Administration of the antioxidants N-acetylcysteine and deferoxamine shortly after murine sepsis induction has shown long-term neuroprotective effects.”

Systemic inflammation disrupts brain networks

Human brain connectome

The human brain connectome

The brain is characterized as a ‘small-world’ network with two levels of connection that are susceptible to disruption by inflammation.

“Biological systems, such as the neuronal network of the human brain have “small-world” properties. Small-world networks have two levels of organization. On the local level, groups of neurons specialized in a specific task form functional modules with high short intramodular connectivity. On the global level, different modules are connected through long intermodular connections. The advantage of the latter type of connections is enhanced computational efficiency through parallel processing of information. Anatomically, long intermodular connections are formed by axonal fiber tracts in the white matter. Long fibers are characterized by high energetic “wiring costs”. To provide the energy for the maintenance of these long fibers the brain is relying on a constant energy supply. Recent findings have elegantly identified oligodendrocyte-derived lactate as the main energetic substrates for axonal maintenance. Consistently, disruption of this oligodendrocyte-neuronal metabolic coupling triggered neurodegeneration. Systemic inflammation poses dramatic challenges to the energetic supply of the brain.”

The brain requires a constant stream of nutrients to maintain its ‘wiring’

Autoimmune driven neuroinflammation, among other insults, can disrupt the delivery of nutrients to neurons and contribute to mitochondrial dysfunction.

“To cover its wiring costs the brain is highly reliant on a constant nutrient supply. Nutrient supply through blood vessels can be compromised through vascular pathologies associated with systemic inflammation…Autoimmune disorders have a chronic course of vascular pathology with acute flares. The most common vascular pathology is the autoantibody-associated antiphospholipid syndrome. Patients with antiphospholipid syndrome display cognitive deficits. MRI studies found diffuse infarctions and white matter lesions in these patients…In line with the concept of high “wiring costs” imposed on the brain by long intermodular connections,Hans Lassmann argues that inflammation in MS causes mitochondrial damage and inability of the brain to maintain neuronal processes. The source of mitochondrial damage is radicals formed as a consequence of inflammation in MS.”

Energy crisis for the brain

Systemic inflammation damages connectivity and fuels mitochondrial dysfunction…

“Taken together these findings indicate that systemic inflammation leads to an energy crisis of the brain that reduces its connectivity. Oxidative stress might be the main mediator of this pathology. Thus, inflammation-induced changes in the brain resemble hallmarks of the aged brain where oxidative damage leads to decreased expression of genes associated with synaptic plasticity and increased expression of stress-response genes. Likewise, the brain during systemic inflammation shows hallmarks of neurodegenerative diseases where oxidative stress and mitochondrial damage have consistently been found.”

Balancing act

Normally astrocytes and neurons talk to each other to keep activation of brain immune cells in check. But this can get out of hand in response to a pathogen resulting in serious damage. Balance is maintained, partly by accepting a certain degree of tolerance for pathogens:

“Brain-resident microglia and peripheral immune cells maintain immune surveillance of brain parenchyma, CSF, and perivascular space for infectious agents or damage-associated milieu changes. In the case of brain infection, complete eradication of some invading pathogens can only be achieved at the cost of irreparable damage to brain tissue. To prevent such damage, the immune system has established active mechanisms of pathogen tolerance. Examples for coexistence-prone pathogens are herpes simplex virus type I or Cryptococcus gattii. A growing body of evidence indicates that not only immune tolerance but also resolution of neuroinflammation is a tightly regulated active immunological process. Taken together, anti-inflammatory brain milieu, pathogen tolerance, and resolution of neuroinflammation require a balanced action between different branches of the immune system.”

Dysregulation causing systemic inflammation drives neurodegeneration

There are a number of mechanisms by which dysregulated systemic inflammation promotes neuroinflammation and neurodegeneration. These in include activation of apoptosis through the inflammasome (inflammation signalling chains):

Apoptosis is one of the main drivers of neurodegeneration. Apoptosis and cell death constantly occur under physiological conditions throughout the human body and cell debris is cleared by immune cells mostly without induction of chronic inflammation. However, during systemic inflammation, apoptosis of stressed cells might further exacerbate the underlying pathology. Activators of apoptosis lead to direct or indirect activation of caspases…inflammatory caspases are crucial for the activation of the innate immune system through the inflammasome…Activation of the innate immune system through the inflammasome is a driver of pathology in age-associated and autoimmune neurodegenerative disorders…these finding show an intricate relationship between inflammation and activation of apoptosis”

Microvesicles (MVs) packed with inflammatory messengers are secreted by peripheral and brain immune cells contribute to neurodegeneration:

“Cellular components of innate immunity can pack and secrete inflammatory messengers in microvesicles (MVs). Peripheral macrophages, as well as brain microglia can secrete inflammasome components (caspase-1, IL-1β, and IL-18) in MVs, and the presence of extravesicular inflammatory inducers (e.g., astrocitic ATP) is sufficient to induce the neurotoxicity by the inflammatory load of MVs.”

This correlates with disease activity in multiple sclerosis and also a significant role in Alzheimer’s disease (AD):

“Recent evidence suggest that MVs play a critical role in the spectrum of AD as well. MVs released by activated microglia participate in the neurodegenerative process of AD by promoting the generation of highly neurotoxic soluble forms of β-amyloid. Based on this collective evidence, it is now clear that EVs produced by peripheral myeloid cells, as well as immune brain cells, are novel and potentially critical biomarkers for neuroinflammatory conditions by providing a link between inflammation and neurodegeneration.”

Inflammation leads to neurodegeneration

Inflammation to neurodegeneration

Immune cells and mediators drive neurodegeneration

Immune cells in both the periphery and the brain can cause neuronal apoptosis through multiple pathways that can be targeted for therapy:

“Various triggers of apoptosis have been described with respect to the brain. Neuronal apoptosis can be directly induced by ROS, pro-inflammatory cytokines or activated immune cells…Additionally, damaged mitochondria are a major source of ROS and mediators of apoptosis. Conversely, inactivation of ROS has anti-apoptotic effects. The inflammatory cytokine TNFα and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly induce neuronal apoptosis. Additionally, intracerebroventricularly injected TNFα was shown to induce depression-like symptoms. Cytokine mediated induction of apoptosis was also observed by IL-1β.”

Immune cells in the brain and the periphery cause neurodegeneration, with evidence that antiinflammatory interventions can oppose neuronal death.

“Sources of cytokines under systemic inflammation are brain resident, paravascular or peripheral immune cells. Furthermore, activated immune cells can directly induce neuronal cell death. Brain-resident microglia convey neuronal toxicity through various mechanisms including secretion of neurotoxic factors, as well as through activation of cyclooxygenase/prostaglandin E2 (COX/PGE2) pathways. In fact, blocking the COX/PGE2 pathway by experimentally deleting the prostaglandine receptor EP2 increases mitochondrial degradation of β-amyloid, potentially opening a new therapeutic avenue for AD.”

When there is systemic inflammation immune cells in the periphery in the body can gain access to the brain through the blood-brain barrier:

Peripheral immune cells can penetrate the BBB under conditions of systemic inflammation and contribute to brain pathology. Cytotoxic T-cells were shown to be directly neurotoxic in autoimmune and aging-associated neurodegenerative disorders of the CNS. Co-localization of T-cells with neurons and neuron-specific cytotoxicity of T-cells was shown in vivo and in vitro.”

Anti-brain antibodies*

Identification of anti-brain antibodies is a key clinical finding that practitioners in a wide range of disciplines should be alert for.

“B-cell-derived anti-brain antibodies have been identified as drivers of brain pathology in various diseases. In the last decade, an increasing number of anti-brain antibodies has been detected that can affect cognition and behavior…Under pathological conditions, antibodies may penetrate the BBB through different mechanisms including local and systemic inflammation, or antigen mediated endocytosis.”

Anti-NMDA antibodies have been receiving much scrutiny for neuropsychiatric and neurodegenerative disorders.

“Furthermore, NMDA-receptor-specific antibodies to the subunit 2 (GluN2) have been found in a subset of SLE patients with neuropsychiatric symptoms. These antibodies are cross-reactive to DNA…DNA–NMDA receptor antibodies preferentially bind the open configuration of the NMDA receptor and augment NMDA receptor-mediated excitatory postsynaptic potentials…Depending on the antibody concentrations, DNA–NMDA receptor antibodies can cause either neuronal dysfunction by transiently enhancing excitatory postsynaptic potentials or can result in neuronal cell death. This evidence could be of high relevance in terms of reversibility of symptoms…Furthermore, anti-brain antibodies were also shown to induce neuropsychiatric symptoms in patients with other autoimmune disorders such as celiac disease or inflammatory bowel diseases. Taken together, anti-brain antibodies were shown to cause neuropsychiatric pathology in different diseases presenting novel therapeutic options.”

Inflammation disrupts neurogenesis

Both generation of new neurons and the support of synaptic health and plasticity are adversely affected by inflammation and this too is an avenue for treatment.

Neurogenesis is a central mechanism required for neuronal maintenance and adaptive plasticity in the healthy and diseased brain. Inflammatory mediators have various effects on neurogenesis. Impairment of neurogenesis was shown in neurodegenerative diseases such as AD and neuropsychiatric disorders such as depression. Interestingly, approved AD drugs and chronic antidepressant treatment induce neurogenesis. Inflammation and microglial activation is detrimental for neurogenesis that can be restored by anti-inflammatory treatment. Moreover, microglia are not only involved in the maintenance of the neurogenic niche but also in synaptic maintenance. Of interest, systemic immune cells were shown to be involved in regulation of neurogenesis. CD4+ T-cells were shown to promote while CD8+ T-cells impair proliferation of neural progenitor cells…one may speculate that neuropsychiatric symptoms elicited by chronic inflammation may be driven by detrimental changes of neuronal homeostasis. Thus, specific immune modulatory treatment might be beneficial.”

Inflammation is a core issue for brain health, cognition and mood

Case management of neuropsychiatric and neurodegenerative disorders requires discerning and treating the causes of chronic inflammation on an individual case basis. The authors conclude:

Sustained systemic inflammation is a common feature of many autoimmune disorders, and is present in most sepsis survivors. Cognitive impairment is common in sepsis survivors, as well as patients suffering from chronic inflammatory conditions…Moreover, systemic inflammation occurring in a susceptible brain (e.g., patients with AD) may lead to even further disruption in quality of life and activities of daily living. Up to 95% of patients with SLE develop neuropsychiatric dysfunction…In patients with rheumatoid arthritis, the baseline vagal tone of is persistently low, suggesting a possible mechanism for persistent inflammation. Those examples indicate that the normal neuroimmune cross-talk in health can become deleterious during disease, particularly in a primed brain – one with preexistent damage. Recently, cellular, molecular, environmental, and genetic components have been linked to the persistent brain dysfunction of systemic inflammation. Here, we have discussed mechanistic evidence for the intricate interrelation between inflammation and neurodegeneration. Identification of druggable targets derived from these mechanisms holds the promise to prevent long-term disability and improve the quality of life in patients with chronic inflammatory conditions.”

*Note: Transglutaminase-6 antibodies are included in the Wheat/Gluten Proteome Reactivity & Autoimmunity array from Cyrex Laboratories.

Traumatic brain injury and chronic neuroinflammation

Neuropsychiatric Disease and TreatmentTraumatic brain injury (TBI) even in it’s milder forms can initiate a process of chronic neuroinflammation that causes a range of chronic neurodegenerative disorders. The authors of a paper just published in Neuropsychiatric Disease and Treatment detail the secondary injury cascades that exacerbate the damage and can lead to chronic traumatic brain injury.

Mild TBI, sometimes referred to as concussion, is the most prevalent TBI. Although TBI has been traditionally considered an acute injury, accumulating clinical and laboratory evidence has recognized the chronic pathology of the disease. Indeed, TBI can manifest many symptoms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease…Accumulating laboratory and clinical evidence has implicated neuroinflammation in both acute and chronic stages of TBI, suggesting this secondary cell death pathway may be the key to the disease pathology and treatment…”

Neuroinflammation in traumatic brain injury stands out as a target of inquiry:

“Here, we focus on neuroinflammation, which closely manifests immediately after TBI onset, and equally important, it persists in the chronic stages of the disease, making it an appealing target for understanding TBI pathology and its treatment.”

Mild traumatic brain injury may cause a variety of symptoms to persist

Clinicians need to be alert to a range of possible symptoms long after the original injury.

“Most patients fully recover in a couple hours or days, although it may take a couple of weeks. However, depending on the severity of the injury, there are some cases in which victims do not recover and the symptoms persist for years….Clinical manifestations of mild TBI consist of a combination of physical and neuropsychiatric symptoms, which include behavioral and cognitive disorders…Of the physical symptoms of TBI, headaches are the most common, with around 25%–90% of post–mild TBI patients reporting it. Dizziness and nausea are other common symptoms, along with fatigue, sleep disruption, hearing problems, and visual disturbances. As a result of damage to the frontal or temporal lobe, TBI patients are also prone to seizures, which may present a challenge for diagnosis and treatment (ie, differential diagnosis between TBI and epilepsy).”

Chronic cognitive and behavioral disorders from mild traumatic brain injury

The cascade of neurodegenerative effects stemming from mild traumatic brain injury are tragically life altering.

“Cognitive disorders after TBI primarily include attention deficit, memory problems, and executive dysfunction. Attention deficit is very common and interferes with other functions, making daily tasks harder than before…These include irritability, mood changes, aggression, impulsivity, self-centered behavior, and poor persistence. Other symptoms related to TBI are depression (sadness, low energy and motivation, not liking oneself, hopelessness), anxiety, and posttraumatic stress disorder. In addition, as noted earlier, TBI may increase the risk of developing Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative diseases in the long term.”

Primary and secondary waves of injury

Both short and long term cascades of damage occur when the brain is subject to trauma.

“The initial insult first leads to a primary injury caused by the mechanical damage from shearing, tearing, and/or stretching of neurons, axons, glia, and blood vessels…The primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes. This occurs within seconds to minutes after the traumatic insult and can last for days, months, or years. It often leads to progressive neurodegeneration and delayed cell death, exacerbating the damage from the primary injury. The secondary wave is mainly detected in the injury site and surrounding tissue, although neurodegeneration in brain areas located far from the primary impact has recently been recognized

The secondary wave consists of excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier (BBB) disruption, and inflammation. All these processes contribute to neurological deficits separately, but at the same time, these cell death processes interact, worsening the progressive outcome of TBI.”

Excitotoxicity in traumatic brain injury

Substances released by damaged neurons cause brain cells to be stimulated to death.

“…injured nerve cells secreting large amounts of intracellular glutamate into the extracellular space…overstimulates the AMPA and NMDA receptors of surrounding nerve cells. These receptors stay activated, allowing an influx of sodium and calcium ions into the cell. The high concentration of calcium ions in the cytosol leads to the activation of protein phosphatases, phospholipases, and endonucleases. Eventually, the DNA is fragmented, and structures and membranes of the cell are deteriorated. This results in cell death through a hybrid form of apoptosis and necrosis. The overstimulation of glutamate receptors also results in the increased production of nitric oxide, free radicals, and pro-death transcription factors.”

ROS in traumatic brain injury

A damaging increase in free radical reactive oxygen species (ROS) and reactive nitrogen species (RON), which are normally kept at a low level in the brain by antioxidants and enyzmes, also contributes to neuronal cell death.

“After TBI, a significant increase in ROS and impairment of antioxidants that lower the levels is seen. When the generation of ROS/RON is too large, it leads to major cell dysfunction, as its oxidative capabilities damage all biomolecules. ROS cause lipoperoxidation of the cell membrane, which results in the dysfunction of many structures and organelles, such as the mitochondria and oxidizing proteins that affect membrane pores. It may also fragment DNA, causing mutations. ROS are also related to the infiltration of neutrophil, which induces an inflammatory response that, in turn, increases the generation of ROS. Overall, oxidative stress cascade results in large neuronal cell death.”

Mitochondrial dysfunction in mild TBI

Mitochondrial dysfunction, typically a contributing factor to neurodegeneration in general, also plays a role in neuronal cell death and chronic loss of brain function following traumatic brain injury.

“After TBI, the stabilizing mechanisms of levels of ROS become impaired, resulting in increased concentrations. Lipid peroxidation-mediated oxidative damage to the mitochondrial membrane negatively affects its structure and function. The mitochondria also works as a calcium ion buffer, releasing and absorbing the ions as needed to maintain homeostasis. However, when the calcium ion load becomes too large from excitotoxicity, the function of the mitochondria becomes impaired. The mitochondrial permeability transition pore, associated with the mitochondrial inner membrane, is a calcium ion-dependent pore. With the excess calcium ions, the pore stays active, disrupting the mitochondrial membrane potential. Without a membrane potential, the mitochondria is unable to produce ATP, and the ATP synthase may actually consume ATP instead of producing it. With mitochondrial break down, toxins and apoptotic factors are released into the cell, activating the caspase-dependent apoptosis. This causes the cell to commit suicide.”

Blood-brain barrier disruption

Loss of blood brain barrier (BBB) integrity also contributes to brain cell death following TBI.

“BBB dysfunction is related to neuronal cell death and cognitive decline and limits the effectiveness of therapies. Its dysfunction triggers many other secondary injuries, including cell death, oxidative stress, and inflammation, causing the brain to swell, with higher intracranial pressure and ischemia. The primary injury disrupts the tight junctions, allowing an influx of peripheral immune cells and circulating factors (albumin, thrombin, and fibrinogen). These events affect the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability. One of the underlying mechanisms regarding BBB dysfunction after TBI is the up-regulation of protein matrix metallopeptidase 9 (MMP-9). This digests the tight junctions, disrupting its proper function. BBB breakdown also allows an influx of larger molecules such as leukocytes that increase the osmotic force in the brain. This results in edema and higher intracranial pressure, which are directly related to ischemia and further cell death.”

 Neuroinflammation, the ‘big enchilada’

Neuroinflammation in TBI

Red line = damaging neuroinflammation, Green solid = pro-survival inflammation, green dotted = treatment, arrow = initiation of treatment.

Brain inflammation may be the leading contributor to accelerated loss of brain cells in most forms of neurodegeneration. In traumatic brain injury it is triggered immediately after impact and can continue for many years.

“After the initial injury, an endogenous inflammatory response is triggered to defend the injury site from invading pathogens and to repair the damaged cells. The complement is activated to perform these functions and recruits inflammatory cells into the intrathecal compartment. The activation of the complement is also accompanied by the infiltration of neutrophils, monocytes, and lymphocytes across the BBB. These secrete prostaglandins, free radicals, proinflammatory cytokines, and other inflammatory mediators that, in turn, up-regulate the expression of chemokines and cell adhesion molecules. This results in immune cells and microglia mobilizing into the brain parenchyma.”

While the microglial cells perform important positive functions that limit damage and sequester the injured tissue, they fire up neuroinflammation by over-reacting. This is particularly true of the M1 phenotype of glial cells.

“…microglial activation in TBI is excessive, and proinflammatory cytokines such as tumor necrosis factor (TNF)- , IL-1 , IL-6, IL-12, and interferon are released. The up-regulation of these cytokines increases the permeability of the BBB by higher expression of cell adhesion molecules in the endothelial cells and by an increased production of chemokines. This results in an increased inflammatory response. Sustained microglial activation also produces neurotoxic molecules and free radicals, which lead to other mechanisms of secondary cell death…In addition, activated microglial cells increase the expression of major histocompatibility complex class II (MHCII ), which is directly correlated to neurodegeneration.”

Astrocytes too exert beneficial effects by increasing brain-derived neutrophilic factors (BDNF) and regulating extracellular glutamate to reduce excitotoxicity. However…

“…when the presence of astrocytes is too large and they become overactivated, it can lead to detrimental effects in the brain. The astrocytes secrete inhibitory extracellular matrix, building a dense physical and chemical barrier surrounding the injury site (glial scar), which encapsulates and isolates the axons. This protects the remaining healthy brain from the neurotoxic environment of the injury site, but it also interferes and prevents the regeneration and repair of the damaged tissue.”

What to do?

A rational treatment plan should include the various remedial measures that target all of these processes:

  • Wind down glutamate excitotoxicity
  • Oppose oxidative stress
  • Support mitochondrial function
  • Help repair the blood-brain barrier
  • Calm neuroinflammation

These processes play a role in neurodegeneration from other causes besides traumatic brain injury. The clinician should have a repertoire of remedial measures at hand to address them. Past and future posts report on advances in treatment. Calming neuroinflammation plays a premiere role.”

“It takes considerably more time for the inflammatory cells to reach the injured brain and contribute to the secondary cell death damage than it takes other secondary death mechanisms, such as glutamate excitotoxicity. This delayed onset provides an extended window of opportunity in which treatments can be administered, greatly increasing the chances of a successful intervention and preventing further damage.”

One cardinal point must be kept in mind: there is a beneficial ‘housecleaning’ side to neuroinflammation so antiinflammatory therapies should not be overdone.

“Immune cells, astrocytes, cytokines, and chemokines are all necessary components for brain repair, and it is their excessive levels that contribute to the secondary cell death damage in TBI…When considering treatments for neuroinflammation in TBI, it is important to note that inflammation has both beneficial and detrimental effects. Prior studies have shown that high doses of antiinflammatory agents actually lead to worse outcomes. In addition to inhibiting the detrimental effects of neuroinflammation, these robust treatments may also retard the beneficial ones.”

Judicious application of natural anti-inflammatory agents to minimize side-effects along with other measures guided by objective measurements is a standard for treating traumatic brain injury that can be applied to other neurodegenerative disorders as well.

Benzodiazepines associated with increased Alzheimer’s risk

BMJBenzodiazepines are well known to be deleterious to brain health with more than very short-term use. Research just published in BMJ (British Medical Journal) presents evidence that use of benzodiazepines longer than three months to treat anxiety or insomnia is associated with a substantial increase in the risk of Alzheimer’s disease.The authors note urgent public health concerns regarding dementia:

Rising tide of dementia

Dementia is currently the main cause of dependency in older people and a major public health concern affecting about 36 million people worldwide. Because of population growth and demographic ageing, this number is expected to double every 20 years and to reach 115 million in 2050, resulting in tragic human consequences and social costs. As there are no effective treatments, the search for putative modifying factors remains a priority. Several studies have shown that benzodiazepine use could be one of these. This class of drugs is mainly used to treat anxiety or insomnia. Prevalence of use among elderly patients is consistently high in developed countries and ranges from 7% to 43%. International guidelines recommend short term use, mainly because of withdrawal symptoms that make discontinuation problematic. Although the long term effectiveness of benzodiazepines remains unproved for insomnia and questionable for anxiety, their use is predominantly chronic in older people.”

Benzodiazepines and dementia

“While the acute deleterious effects of benzodiazepines on memory and cognition are well documented, the possibility of an increased risk of dementia is still a matter of debate.”

So they investigated the relation between the risk of Alzheimer’s disease with exposure to benzodiazepines that started at least five years before, in 1796 subjects who ended up developing Alzheimer’s who were matched with 7184 controls and found:

Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density 1.32 for 91-180 prescribed daily doses and 1.84 for >180 prescribed daily doses and with the drug half life (1.43) for short acting drugs and 1.70 for long acting ones.”

Benzodiazepines duration and discontinuation

MedscapeA comment in Medscape Family Medicine states:

“The investigators note that although these medications are important treatment options, clinicians should “comply with good practice guidelines” and prescribe benzodiazepines for as short a time as possible. In addition, use should not exceed 3 months.”

Note: Benzodiazepines in long term use should never be discontinued abruptly and without the guidance of a clinician due to the likelihood of serious adverse withdrawal effects.

The authors conclude:

Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.”

Nigella sativa, a true ‘wonder medicine’?

Nigella sativa flower and seedsNigella sativa, also known as black cumin, produces seeds with a mind-boggling wealth of medicinal virtues. For colleagues and others who may not be familiar with the abundance of scientific evidence for the use of Nigella sativa seed extract in clinical practice, this selection of citations serves as an introduction to its wide range of indications.

An illustrious history

Asian Pacific Journal of Tropical MedicineTraditional uses of Nigella sativa are surveyed in a paper published in the Asian Pacific Journal of Tropical Medicine:

Nigella sativa (N. sativa) (Family Ranunculaceae) is a widely used medicinal plant throughout the world. It is very popular in various traditional systems of medicine like Unani and Tibb, Ayurveda and Siddha. Seeds and oil have a long history of folklore usage in various systems of medicines and food. The seeds of N. sativa have been widely used in the treatment of different diseases and ailments. In Islamic literature, it is considered as one of the greatest forms of healing medicine. It has been recommended for using on regular basis in Tibb-e-Nabwi (Prophetic Medicine). It has been widely used as antihypertensive, liver tonics, diuretics, digestive, anti-diarrheal, appetite stimulant, analgesics, anti-bacterial and in skin disorders. Extensive studies on N. sativa have been carried out by various researchers and a wide spectrum of its pharmacological actions have been explored which may include antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective, antioxidant properties, etc. Due to its miraculous power of healing, N. sativa has got the place among the top ranked evidence based herbal medicines. This is also revealed that most of the therapeutic properties of this plant are due to the presence of thymoquinone which is major bioactive component of the essential oil. The present review is an effort to provide a detailed survey of the literature on scientific researches of pharmacognostical characteristics, chemical composition and pharmacological activities of the seeds of this plant.”

Critical Reviews in Food Science and NutritionA paper published in the journal Critical Reviews in Food Science and Nutrition also suggests Nigella sativa’s wide scope of use:

“…It possesses a nutritional dense profile as its fixed oil (lipid fraction), is rich in unsaturated fatty acids while essential oil contains thymoquinone and carvacrol as antioxidants. N. sativa seeds also contain proteins, alkaloids (nigellicines and nigelledine), and saponins (α-hederin) in substantial amounts. Recent pharmacological investigations suggested its potential role, especially for the amelioration of oxidative stress through free radical scavenging activity, the induction of apoptosis to cure various cancer lines, the reduction of blood glucose, and the prevention of complications from diabetes. It regulates hematological and serological aspects and can be effective in dyslipidemia and respiratory disorders. Moreover, its immunopotentiating and immunomodulating role brings balance in the immune system. Evidence is available supporting the utilization of Nigella sativa and its bioactive components in a daily diet for health improvement. This review is intended to focus on the composition of Nigella sativa and to elaborate its possible therapeutic roles as a functional food to prevent an array of maladies.”

Anti-inflammatory activity

Molecular Biology ReportsChronic inflammation is a hallmark of most chronic degenerative diseases. A study published in Molecular Biology Reports demonstrates that Nigella sativa reduces inflammation triggered by LPS (lipopolysaccharide), of particular relevance for autoimmunity.

“Inflammation has an important role in many diseases such as cystic fibrosis, allergies and cancer. The free radicals produced during inflammation, can induce gene mutations and posttranslational modifications of cancer related proteins. Nigella sativa L. (N. sativa) is herbaceous plant and commonly used as a natural food. It has many pharmacological effects including antibacterial, antifungal, antitumor, analgesic, antipyretic activity. The aim of this study was to investigate the anti-inflammatuar and anti-oxidant activity of N. sativa in acute inflammation. Thus we used the experimental lipopolysaccharides (LPS)-induced model. Intraperitoneal LPS 1 mg/kg was administered to groups. N. sativa (500 mg/kg) and essential oil (5 ml/kg) were given orally to treatment groups, after 24-h of intraperitoneal LPS-injection. To determine the lung inflammation, 18F-fluoro-deoxy-d-glucose (0.8 ml/kg) was administrated under the anesthesia before the 1 h of PET-scanning. After the FDG-PET, samples were collected. Lung and liver18F-FDG-uptake was calculated. Serum AST, ALT, LDH and hcCRP levels were determined and liver, lung and erythrocyte SOD, MDA and CAT levels were measured. Liver and lung NO and DNA fragmentation levels were determined. MDA levels were decreased in treated inflammation groups whereas increased in untreated inflammation group. SOD and CAT activities in untreated inflammation group were significantly lower. According to the control group, increased AST and ALT levels were found in untreated inflammation group. 18F-FDG uptake of inflammation groups were increased when compare the control group… We conclude that, in LPS-induced inflammation, N. sativa have therapeutic and anti-oxidant effects.”

Immunomodulatory effects of Nigella sativa

Chinese Journal of Integrative MedicineA fascinating study in the Chinese Journal of Integrative Medicine offers evidence that Nigella sativa, beyond having simply an anti-inflammatory effect, is an immunomodulator that may help to restore healthier immune regulation:

“Cells isolated from human PBMCs which were treated with methanolic extract of NS for 48 h into two separate environments (PHA and non-PHA stimulated). Flow cytometry (for T helper/inducer cells and natural killer cells) and real time-polymerase chain reaction (PCR) assays for a few selected proinflammatory gene expressions were performed. Extracts from NS had an immunostimulating effect on non-PHA-stimulated proliferation of human PBMCs. In contrast, immunosuppressive activity was observed on PHA-stimulated proliferation of human PBMCs.”

Antimicrobial activity

BioMed Research InternationalNigella sativa has also shown good effect in the treatment of infections. A study recently published in Biomed Research International validates its antibacterial and antifungal properties:

“…major components in black cumin essential oils which were thymoquinone (37.6%) followed by p-cymene (31.2%), α-thujene (5.6%), thymohydroquinone (3.4%), and longifolene (2.0%), whereas the oleoresins extracted in different solvents contain linoleic acid as a major component….The essential oil showed up to 90% zone inhibition against Fusarium moniliforme in inverted petri plate method. Using agar well diffusion method for evaluating antibacterial activity, the essential oil was found to be highly effective against Gram-positive bacteria.”

The authors summarize their findings by concluding:

“The results obtained in antimicrobial investigations of black cumin oil and oleoresins were in good agreement with the previous reported work…Seeds of black cumin seem to possess magical properties and have been worked out extensively. This study revealed that black cumin essential oil and its oleoresins constitute a good alternative source of essential fatty acids compared with common vegetable oil. The present results showed that essential oil and oleoresins of black cumin exhibited higher antioxidant activity than synthetic antioxidants. These findings could be used to prepare multipurpose products for pharmaceutical applications and its usage as dietary source of antioxidant should be considered largely for alleviating and ameliorating diseases.”

World Journal of GastroenterologyPotent antiviral effects of Nigella sativa are in evidence in a study published in the World Journal of Gastroenterology on hepatitis C:

“Thirty patients with hepatitis C virus (HCV) infection, who were not eligible for IFN/ribavirin therapy, were included in the present study…Various parameters, including clinical parameters, complete blood count, liver function, renal function, plasma glucose, total antioxidant capacity (TAC), and polymerase chain reaction, were all assessed at baseline and at the end of the study. Clinical assessment included: hepato and/or splenomegaly, jaundice, palmar erythema, flapping tremors, spider naevi, lower-limb edema, and ascites. N. sativa was administered for three successive months at a dose of (450 mg three times daily). Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study.”

The improvements noted were outstanding:

“N. sativa administration significantly improved HCV viral load. After N. sativa administration, the following laboratory parameters improved: total protein, albumin, red blood cell count, and platelet count. Fasting blood glucose and postprandial blood glucose were significantly decreased in both diabetic and non-diabetic HCV patients. Patients with lower-limb edema decreased significantly from baseline compared with after treatment. Adverse drug reactions were unremarkable except for a few cases of epigastric pain and hypoglycemia that did not affect patient compliance.”

Clinicians involved in case management of HCV should note their conclusion:

N. sativa administration in patients with HCV was tolerable, safe, decreased viral load, and improved oxidative stress, clinical condition and glycemic control in diabetic patients.”

 Amelioration of metabolic disorders

Plant Foods for Human NutritionNigella sativa possesses remarkable properties that improve metabolic disorders ranging including insulin resistance and diabetes, obesity, and liver fibrosis. From a paper in Plant Foods for Human Nutrition:

“Obesity is closely associated with increased incidence of cardiovascular diseases, cancer, insulin resistance, and immune dysfunction, and thus obesity-mitigation strategies should take into account these secondary pathologies in addition to promoting weight loss. Recent studies indicate that black cumin (Nigella sativa) has cardio-protective, anti-cancer, anti-diabetic, antioxidant, and immune-modulatory properties.”

 Diabetes

Evidence-Based Complementary and Alternative MedicineEvidence for its benefit in diabetes is offered in a study published in Evidence-Based Complementary and Alternative Medicine:

“The main objective of this instant study was to explore the antidiabetic potential of Nigella sativa fixed oil (NSFO) and essential oil (NSEO). Three experimental groups of rats received diets during the entire study duration, that is, D1 (control), D2 (NSFO: 4.0%), and D3 (NSEO: 0.30%). Experimental diets (NSFO & NSEO) modulated the lipid profile, while decreasing the antioxidant damage. However, production of free radicals, that is, MDA, and conjugated dienes increased by 59.00 and 33.63%, respectively, in control. On the contrary, NSFO and NSEO reduced the MDA levels by 11.54 and 26.86% and the conjugated dienes levels by 32.53 and 38.39%, respectively. N. sativa oils improved the health and showed some promising anti-diabetic results.”

BMC Complementary & Alternative MedicineAnother study on Nigella sativa and diabetes was recently published in BMC Complementary and Alternative Medicine.

Nigella sativa fixed (NSFO) and essential (NSEO) oils have been used to treat diabetes mellitus and its complications. Present study was undertaken to explore and validate these folkloric uses…Sprague dawley rats having streptozotocin (STZ) induced diabetes mellitus were used to assess the role of NSFO and NSEO in the management of diabetes complications.”

Of note is its ability to increase levels of glutathione:

“The results indicated that STZ decreased the glutathione contents (25.72%), while NSFO and NSEO increased the trait significantly. Experimental diets increased the tocopherol contents and enhanced the expression of hepatic enzymes. Correlation matrix further indicated that antioxidant potential is positively associated responsible for the modulation of hepatic enzymes and the decrease of the nitric oxide production thus controlling the diabetes complications.”

Nigella sativa lowers cholesterol

Advanced Pharmaceutical BulletinCholesterol along with blood glucose was lowered in a study on Nigella sative for metabolic syndrome in menopausal women published in the Advanced Pharmaceutical Bulletin:

“Thirty subjects who were menopausal women within the age limit of 45-60 were participated in this study and randomly allotted into two experimental groups. The treatment group was orally administered with N. sativa seeds powder in the form of capsules at a dose of 1g per day after breakfast for period of two months and compared to control group given placebo…significant improvement was observed in total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and blood glucose…These results suggested that treatment with N. sativa exert a protective effect by improving lipid profile and blood glucose which are in higher risk to be elevated during menopausal period.”

Journal of Translational MedicineImprovements in hypercholesterolemia in menopause were also documented in a study recently published in the Journal of Translational Medicine:

“In this study, Nigella sativa was evaluated for its hypolipidemic effects among menopausal women. In a randomised trial, hyperlipidemic menopausal women were assigned to treatment (n = 19) or placebo groups (n = 18), and given N. sativa or placebo for two months after their informed consents were sought. At baseline, blood samples were taken and at one month intervals thereafter until one month after the end of the study…The results showed that N. sativa significantly improved lipid profiles of menopausal women (decreased total cholesterol, low density lipoprotein cholesterol and triglyceride, and increased high density lipoprotein cholesterol) more than the placebo treatment over 2 months of intervention.”

These benefits persisted for a month after treatment with Nigella sativa was discontinued:

One month after cessation of treatment, the lipid profiles in the N. sativa-treated group tended to change towards the pretreatment levels.”

The authors conclude:

“N. sativa is thought to have multiple mechanisms of action and is cost-effective. Therefore, it could be used by menopausal women to remedy hypercholesterolemia, with likely more benefits than with single pharmacological agents that may cause side effects. The use of N. sativa as an alternative therapy for hypercholesterolemia could have profound impact on the management of CVD among menopausal women especially in countries where it is readily available.”

International Journal of Preventive MedicineAnd a study in the International Journal of Preventive Medicine documented improvements in lipid metabolism and oxygen utilization:

“In this randomized, double-blind, controlled trial…20 sedentary overweight females were divided into two groups and assigned to N. sativa supplementation (N. sativa capsules) or a placebo for the 8 weeks, both groups participated in an aerobic training program (3 times/week)…. Blood lipids and VO2 max were determined at baseline and at the end of 8 weeks…N. sativa supplementation lowered total cholesterol (TC), triglyceride, low-density lipoprotein (LDL) and body mass index and increased high density lipoprotein (HDL) and VO2 max.”

It’s worth noting that the diet of the study subjects remained the same:

Since we asked all subjects not to change their usual daily diet, it seems that this changes may be due to the result of consuming black seeds and regular aerobic training.”

Interestingly in regard to lowering cholesterol:

“The hypotriglyceridemic effect of N. sativa is possibly due to its choleretic activity. The choleretic function of N. sativa is either by reducing the synthesis of cholesterol by hepatocytes or by decreasing its fractional reabsorption from the small intestine.”

Nigella sativa’s thymoquinone ameliorates liver fibrosis

International ImmunopharmacologyWith the proliferation of NAFLD and NASH medicines that sustainably alleviate hepatic fibrosis are in urgent need. A study published in International Immunopharmacology offers evidence that thymoquinone, a principal compound in Nigella sativa, has potent hepatic anti-fibrotic effects:

Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. In the present study, we investigated the anti-fibrotic mechanism of TQ in lipopolysaccharide (LPS)-activated rat hepatic stellate cells line, T-HSC/Cl-6. T-HSC/Cl-6 cells were treated with TQ (3.125, 6.25 and 12.5 μM) prior to LPS (1 μg/ml). Our data demonstrated that TQ effectively decreased activated T-HSC/Cl-6 cell viability. TQ significantly attenuated the expression of CD14 and Toll-like receptor 4 (TLR4). TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) phosphorylation. The expression of α-SMA and collagen-I were significantly decreased by TQ. Furthermore, TQ decreased X linked inhibitor of apoptosis (XIAP) and cellular FLIP (c-FLIPL) expression, which are related with the regulation of apoptosis. Furthermore, TQ significantly increased the survival against LPS challenge in d-galactosamine (d-GlaN)-sensitized mice, and decreased the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were in line with in vitro results. Our data demonstrated that TQ attenuates liver fibrosis partially via blocking TLR4 expression and PI3K phosphorylation on the activated HSCs. Therefore, TQ may be a potential candidate for the therapy of hepatic fibrosis.

A follow-up study published recently in the same journal added more evidence to Nigella sativa’s benefits for hepatic fibrosis:Hepatic fibrosis attenuated by thymoquinone

“The current study was conducted to investigate the anti-fibrotic effect and its possible underlying mechanisms of thymoquinone (TQ) against hepatic fibrosis in vivo. TQ is the major active compound derived from the medicinal Nigella sativa. Liver fibrosis was induced in male Kunming mice by intraperitoneal injections of thioacetamide (TAA, 200 mg/kg). Mice were treated concurrently with TAA alone or TAA plus TQ (20 mg/kg or 40 mg/kg) given daily by oral gavage. Our data demonstrated that TQ treatment obviously reversed liver tissue damage compared with TAA alone group, characterized by less inflammatory infiltration and accumulation of extracellular matrix (ECM) proteins. TQ significantly attenuated TAA-induced liver fibrosis, accompanied by reduced protein and mRNA expression of α-smooth muscle actin (α-SMA), collagen-І and tissue inhibitor of metalloproteinase-1 (TIMP-1). TQ downregulated the expression of toll-like receptor 4 (TLR4) and remarkably decreased proinflammatory cytokine levels as well. TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) phosphorylation. Furthermore, TQ enhanced the phosphorylation adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B (LKB)-1. In conclusion, TQ may reduce ECM accumulation, and it may be at least regulated by phosphorylation of AMPK signaling pathways, suggesting that TQ may be a potential candidate for the therapy of hepatic fibrosis.

 Protection against diabetic kidney damage

Ultrastructural PathologyThymoquinone in Nigella sativa also reduced experimentally induced kidney damage in models of diabetes as reported in a study published in Ultrastructural Pathology:

“Diabetic rats exhibited morphological changes in both renal glomeruli and tubules with immunohistochemical expression of the mesenchymal markers Fsp1, desmin, and MMP-17 and disappearance of the epithelial marker ZO-1 largely in the glomeruli of diabetic kidneys. Treatment with TQ significantly attenuated renal morphological and immunohistochemical changes in STZ-induced diabetic ratsThymoquinone has protective effects on experimental diabetic nephropathy. Both mesenchymal and epithelial markers serve as excellent predictors of early kidney damage and indicators of TQ responsiveness in STZ-induced diabetic nephropathy.”

Hypertension and Oxidative Stress

Regarding the anti-hypertensive effects of Nigella sativa, from a paperEvidence-Based Complementary and Alternative Medicine in Evidence-Based Complementary & Alternative Medicine:

Excessive production of reactive oxygen species reduces nitric oxide bioavailability leading to an endothelial dysfunction and a subsequent increase in total peripheral resistance…Nigella sativa (NS) and its active constituents have been documented to exhibit antioxidant, hypotensive, calcium channel blockade and diuretic properties which may contribute to reduce blood pressure. This suggests a potential role of NS in the management of hypertension…”

Protection Against Heart Damage

Pakistan Journal of Pharmaceutical SciencesNot surprisingly, thymoquinone in Nigella sativa appears to exert protective effects against heart damage associated with coronary insufficiency and stress as documented by a study in the Pakistan Journal of Pharmaceutical Sciences. Here again the beneficial effects include support for glutathione:

“Myocardial injury constitutes a major cause of morbidity and mortality in humans. Present study aimed to investigate protective role of thymoquinone, which is an active principle of Nigella sativa (N. sativa) seed (Commonly called as black seed), in isoproterenol induced myocardial injury, a classical example of excess catecholamines related coronary insufficiency and stress cardiomyopathy. Thymoquinone, in olive oil, was administered orally (12.5, 25 and 50mg/kg) to three groups of Wistar albino rats for 7 days, while two control groups were given plain olive oil. Thereafter, thymoquinone receiving groups and one control group were injected, subcutaneously, with isoproterenol (125mg/kg) for 2 days. Myocardial injury was assessed by biochemical markers (plasma LDH, TBARS, GR & SOD and myocardial GSH/GSSG ratio) and cardiac histopathology. Plasma LDH, TBARS and GR increased in control groups receiving isoproterenol, while there was a dose related decrease in these markers in thymoquinone treated groups, down to levels in controls given olive oil only. Decrease in plasma SOD and myocardial GSH/GSSG ratio and histological changes produced with isoproternol were also reversed in thymoquinone treated rats. Results of our study revealed that thymoquinone protects the heart from injury induced by isoproterenol.”

Anti-cancer effects of Nigella sativa

Drug Discovery TodayThere is a wealth of evidence supporting the use Nigella sativa and its active compound thymoquinone as an adjunctive treatment in numerous malignancies as noted in a paper published earlier this year in Drug Discovery Today:

“Thymoquinone (TQ), the main active constituent of black seed essential oil, exhibits promising effects against inflammatory diseases and cancer. TQ, modulates signaling pathways that are key to cancer progression, and enhances the anticancer potential of clinical drugs while reducing their toxic side effects. Considering that TQ was isolated 50 years ago, this review focuses on TQ’s chemical and pharmacological properties and the latest advances in TQ analog design and nanoformulation. We discuss our current state of knowledge of TQ’s adjuvant potential and in vivo antitumor activity and highlight its ability to modulate the hallmarks of cancer.

  • This year marks 50 years since thymoquinone was isolated from black seed.
  • Thymoquinone has had a long history of battling cancer in vitro and in vivo.
  • Thymoquinone modulates nine of the ten hallmarks of cancer.”

American Journal of Chinese MedicineA paper in the American Journal of Chinese Medicine reviews Nigella sativa’s anticancer activities:

“…quite a few pharmacological effects of N. sativa seed, its oil, various extracts and active components have been identified to include immune stimulation, anti-inflammation, hypoglycemic, antihypertensive, antiasthmatic, antimicrobial, antiparasitic, antioxidant and anticancer effects…A literature search has revealed that a lot more studies have been recently carried out related to the anticancer activities of N. sativa and some of its active compounds, such as thymoquinone and alpha-hederin. Acute and chronic toxicity studies have recently confirmed the safety of N. sativa oil and its most abundant active component, thymoquinone, particularly when given orally. The present work is aimed at summarizing the extremely valuable work done by various investigators on the effects of N. sativa seed, its extracts and active principles against cancer. Those related to the underlying mechanism of action, derivatives of thymoquinone, nano thymoquinone and combinations of thymoquinone with the currently used cytotoxic drugs are of particular interest.”

Thymoquinone mechanisms of actionA paper in the African Journal of Traditional, Complementary and Alternative Medicines describes its activity against a number of malignancies and the molecular mechanisms involved:

“Nigella sativa has been used as traditional medicine for centuries. The crude oil and thymoquinone (TQ) extracted from its seeds and oil are effective against many diseases like cancer, cardiovascular complications, diabetes, asthma, kidney disease etc. It is effective against cancer in blood system, lung, kidney, liver, prostate, breast, cervix, skin with much safety. The molecular mechanisms behind its anticancer role is still not clearly understood, however, some studies showed that TQ has antioxidant role and improves body’s defense system, induces apoptosis and controls Akt pathway. Although the anti-cancer activity of N. sativa components was recognized thousands of years ago but proper scientific research with this important traditional medicine is a history of last 2∼3 decades…In this article, we have summarized the actions of TQ and crude oil of N. sativa against different cancers with their molecular mechanisms.”

Pharmacognosy ReviewsA review article in Pharmacognosy Review notes the anti-cancer potential implied by numerous investigations:

“Thymoquinone (TQ) is the bioactive phytochemical constituent of the seeds oil of Nigella sativa. In vitro and in vivo research has thoroughly investigated the anticancer effects of TQ against several cancer cell lines and animal models. As a result, a considerable amount of information has been generated from research thus providing a better understanding of the anti-proliferating activity of this compound. Therefore, it is appropriate that TQ should move from testing on the bench to clinical experiments. The purpose of this review is to highlight the potential of TQ as an anticancer agent and the chances of this compound in the clinical treatment of cancer, with special attention on breast cancer treatment.”

Evidence-Based Complementary and Alternative MedicineA paper in Evidence-Based Complementary and Alternative Medicine outlines mechanisms by which thymoquinone in Nigella sativa can act to prevent cancer:

Earlier studies have shown that N. sativa and its constituent thymoquinone (TQ) have important roles in the prevention and treatment of cancer by modulating cell signaling pathways. In this review, we summarize the role of N. sativa and its constituents TQ in the prevention of cancer through the activation or inactivation of molecular cell signaling pathways.”

Upregulation of tumor suppressor gene and inhibition of VEGF, Akt/PI3K pathways:

Upregulation of tumor suppresor geneThymoquinone role in prevention of cancer via modulation of phase I and phase II enzymes:

Thymoquinone's role in cancer prevention

Osteosarcoma, angiogenesis and NF-κB

Oncology ReportsEvidence for thymoquinone’s benefit in osteosarcoma through inhibition of tumor angiogenesis and tumor growth by suppressing NF-κB is offered by a study published in Oncology Reports:

“Recent studies reported that thymoquinone exhibited inhibitory effects on the cell proliferation of several cancer cell lines. This study was performed to investigate the antitumor and anti-angiogenic effects of thymoquinone on osteosarcoma in vitro and in vivo. Our results showed that thymoquinone induced a higher percentage of growth inhibition and apoptosis in the human osteosarcoma cell line SaOS-2 compared to that of control, and thymoquinone significantly blocked human umbilical vein endothelial cell (HUVEC) tube formation in a dose-dependent manner. To investigate the possible mechanisms involved in these events, we performed electrophoretic mobility shift assay (EMSA) and western blot analysis, and found that thymoquinone significantly downregulated NF-κB DNA-binding activity, XIAP, survivin and VEGF in SaOS-2 cells. Moreover, the expression of cleaved caspase-3 and Smac were upregulated in SaOS-2 cells after treatment with thymoquinone. In addition to these in vitro results, we also found that thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing NF-κB and its regulated molecules. Collectively, our results demonstrate that thymoquinone effectively inhibits tumor growth and angiogenesis both in vitro and in vivo. Moreover, inhibition of NF-κB and downstream effector molecules is a possible underlying mechanism of the antitumor and anti-angiogenic activity of thymoquinone in osteosarcoma.”

Cytotoxic prooxidant effects of thymoquinone in copper rich malignant tissues

Cell Death & DiseaseUsing prostate cancer cells, a fascinating study published in Cell Death & Disease demonstrates that thymoquinone has a beneficial prooxidant cytoxic effect in copper-rich malignant tissue:

“Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive…TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher Nigella sativa flower 2concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death.”

Interestingly…

“We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants.”

Inhibition of cell proliferation in liver cancer

Toxicology LettersMarked inhibition of tumor multiplicity in hepatocellular carcinoma was shown in a study published in Toxicology Letters:

“…agents that inhibit cell proliferation and restrain hepatic tumorigenesis through cell cycle regulation have a beneficial effect in the treatment of hepatocellular carcinogenesis. The present study was aimed to investigate the efficacy of thymoquinone (TQ), an active compound derived from the medicinal plant Nigella sativa, on N-nitrosodiethylamine (NDEA) [0.01% in drinking water for 16 weeks]-induced hepatocarcinogenesis in experimental rats. After experimental period, the hepatic nodules, liver injury markers and tumor markers levels were substantially increased in NDEA induced liver tumors in rats. However, TQ (20 mg/kg body weight) treatment greatly reduced liver injury markers and decreased tumor markers and prevented hepatic nodule formation and reduced tumor multiplicity in NDEA induced hepatic cancer bearing rats and this was evident from argyrophilic nucleolar organizer region (AgNORs) staining. Moreover…TQ significantly reduced the detrimental alterations by abrogating cell proliferation, which strongly induced G1/S arrest in cell cycle transition. In conclusion, our results suggest that TQ has a potent anti proliferative activity by regulating the G1/S phase cell cycle transition and exhibits a beneficial role in the treatment of HCC.”

Thymoquinone induces glioblastoma cell death

PLOS ONEA fascinating study in PLoS One demonstrates that thymoquinone is a rare agent that can inhibit autophagy (the cellular ‘housecleaning’ process by which degraded cellular components are removed) to promote malignant cell death in the brain cancer gliosblastoma:

“Glioblastoma is the most aggressive and common type of malignant brain tumor in humans, with a median survival of 15 months. There is a great need for more therapies for the treatment of glioblastoma…TQ has anti-oxidant, anti-inflammatory and anti-neoplastic actions with selective cytotoxicity for human cancer cells compared to normal cells. Here, we show that TQ selectively inhibits the clonogenicity of glioblastoma cells as compared to normal human astrocytes. Also, glioblastoma cell proliferation could be impaired by chloroquine, an autophagy inhibitor, suggesting that glioblastoma cells may be dependent on the autophagic pathway for survival…TQ also caused an accumulation of the LC3-associated protein p62, confirming the inhibition of autophagy. Furthermore, the levels of Beclin-1 protein expression were unchanged, indicating that TQ interferes with a later stage of autophagy. Finally, treatment with TQ induces lysosome membrane permeabilization…which mediates caspase-independent cell death… TQ induced apoptosis…”

Inhibition of autophagy by thymoquinoneThe authors note an important difference between the action of thymoquinone and other cytotoxic therapies:

Ionizing radiation and temozolomide have both been shown to increase a cytoprotective autophagy response in glioblastoma cells, leading to resistant tumors. In addition, many other chemotherapeutics, such as rapamycin, tamoxifen, and etoposide, induce a protective autophagic response in cancer cells. Therefore, inhibitors of autophagy, both alone and in combination with standard therapies, may provide a viable and promising new strategy in cancer treatment…To the best of our knowledge, this report represents the first finding of TQ as an autophagy inhibitor, and provides a platform for which to extend studies in the treatment of glioblastoma with TQ.”

The authors conclude:

“Inhibition of autophagy is an exciting and emerging strategy in cancer therapy. In this vein, our results describe a novel mechanism of action for TQ as an autophagy inhibitor selectively targeting glioblastoma cells.

Nigella sativa induces apoptosis in cervical cancer

Natural Product CommunicationsAccording to a study published in Natural Product Communications, Nigella sativa inhibits proliferation of cervical cancer cells by inducing apoptosis:

“Nigella sativa (NS) showed an 88.3% inhibition of proliferation of SiHa human cervical cancer cells at a concentration of 125 microL/mL methanolic extract at 24 h, and an IC50 value 93.2 microL/mL. NS exposure increased the expression of caspase-3, -8 and -9 several-fold. The analysis of apoptosis by Dead End terminal transferase-mediated dUTP-digoxigenin end labeling (TUNEL) assay was used to further confirm that NS induced apoptosis. Thus, NS was concluded to induce apoptosis in SiHa cell through both p53 and caspases activation. NS could potentially be an alternative source of medicine for cervical cancer therapy.”

Suppression of melanoma metastasis by inhibition of the NLRP3 inflammasome

Toxicology and Applied PharmacologyIn an exciting study published in Toxicology and Applied Pharmacology that has implications for a wide range of conditions, investigators report suppression of metastasis in melanoma inhibiting the proinflammatory activity of the NLRP3 inflammasome:

“The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β and IL-18 secretion. The NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome is constitutively assembled and activated in human melanoma cells. We have examined the inhibitory effect of thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone), a major ingredient of black seed obtained from the plant Nigella sativa on metastatic human (A375) and mouse (B16F10) melanoma cell lines. We have assessed whether thymoquinone inhibits metastasis of melanoma cells by targeting NLRP3 subunit of inflammasomes. Using an in vitro cell migration assay, we found that thymoquinone inhibited the migration of both human and mouse melanoma cells…The inhibition of migration of melanoma cells by thymoquinone was accompanied by a decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1β and IL-18. Treatment of mouse melanoma cells with thymoquinone also inhibited NF-κB activity. Furthermore, inhibition of reactive oxygen species (ROS) by thymoquinone resulted in partial inactivation of NLRP3 inflammasome. Thus, thymoquinone exerts its inhibitory effect on migration of human and mouse melanoma cells by inhibition of NLRP3 inflammasome. Thus, our results indicate that thymoquinone can be a potential immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention of metastatic melanoma.”

Readers will recall that activation of the inflammasome is a mechanism shared by many autoimmune and malignant disorders.

Nigella sativa attenuates iNOS pathway inflammation in liver cancer

Environmental Health and Preventive MedicineBecause iNOS activation of inflammation is a key process in a multitude of inflammatory disorders including a host of autoimmune diseases, a study published in Environmental Health and Preventative Medicine showing value in hepatocellular carcinoma is of is of particular importance:

“Nitric oxide (NO) and inducible nitric oxide synthase enzyme (iNOS) have been implicated in various tumors….Nigella sativa (NS) has been shown to have specific health benefits. The aim of this study was to investigate the in vivo modulation of the iNOS pathway by NS ethanolic extract (NSEE) and the implications of this effect as an antitumor therapeutic approach against diethylnitrosamine (DENA)-induced hepatocarcinogenesis…Serum AFP, NO, TNF-α, and IL-6 levels and iNOS enzyme activity were significantly increased in rats treated with DENA. Significant up-regulation of liver iNOS mRNA and protein expression was also observed. Subsequent treatment with NSEE significantly reversed these effects and improved the histopathological changes in malignant liver tissue which appeared after treatment with DENA, without any toxic effect when given alone.”

This data inspired the authors to conclude:

“These results provide evidence that attenuation of the iNOS pathway and suppression of the inflammatory response mediated by TNF-α, and IL-6 could be implicated in the antitumor effect of NSEE. As such, our findings hold great promise for the utilization of NS as an effective natural therapeutic agent in the treatment of hepatocarcinogenesis.”

Cytotoxic effect against lung cancer

Asian Pacific Journal of Cancer PreventionAuthors of a study just published in the Asian Pacific Journal of Cancer Prevention report that Nigella sativa seed extract significantly reduces the viability of lung cancer cells:

Nigella sativa (N sativa), commonly known as black seed, has been used in traditional medicine to treat many diseases. The antioxidant, anti-inflammatory, and antibacterial activities of N sativa extracts are well known. Therefore, the present study was designed to investigate the anticancer activity of seed extract (NSE) and seed oil (NSO) of N sativa against a human lung cancer cell line…The results showed NSE and NSO significantly reduce the cell viability and alter the cellular morphology of A-549 cells in a concentration dependent manner. The percent cell viability was recorded as 75%, 50%, and 26% at 0.25, 0.5, and 1 mg/ml of NSE by MTT assay and 73%, 48%, and 23% at 0.25, 0.5, and 1 mg/ml of NSE by NRU assay. Exposure to NSO concentrations of 0.1 mg/ml and above for 24 h was also found to be cytotoxic. The decrease in cell viability at 0.1, 0.25, 0.5, and 1 mg/ml of NSO was recorded to be 89%, 52%, 41%, and 13% by MTT assay and 85%, 52%, 38%, and 11% by NRU assay, respectively. A-549 cells exposed to 0.25, 0.5 and 1 mg/ml of NSE and NSO lost their typical morphology and appeared smaller in size. The data revealed that the treatment of seed extract (NSE) and seed oil (NSO) of Nigella sativa significantly reduce viability of human lung cancer cells.

Nigella sativa inhibits breast cancer

PLOS ONEEvidence is mounting for the use of Nigella sativa against breast cancer. Similar to the prooxidant effect described above, a study published in PLoS One describes how thymoquinone inhibits tumor growth and induces apoptosis in breast cancer cells through p38 phosphorylation and ROS production:

“Due to narrow therapeutic window of cancer therapeutic agents and the development of resistance against these agents, there is a need to discover novel agents to treat breast cancer. The antitumor activities of thymoquinone (TQ), a compound isolated from Nigella sativa oil, were investigated in breast carcinoma in vitro and in vivo. Cell responses after TQ treatment were assessed by using different assays including MTT assay, annexin V-propidium iodide staining, Mitosox staining and Western blot. The antitumor effect was studied by breast tumor xenograft mouse model, and the tumor tissues were examined by histology and immunohistochemistry. The level of anti-oxidant enzymes/molecules in mouse liver tissues was measured by commercial kits. Here, we show that TQ induced p38 phosphorylation and ROS production in breast cancer cells. These inductions were found to be responsible for TQ’s anti-proliferative and pro-apoptotic effects. Moreover, TQ-induced ROS production regulated p38 phosphorylation but not vice versa. TQ treatment was found to suppress the tumor growth and this effect was further enhanced by combination with doxorubicin. TQ also inhibited the protein expression of anti-apoptotic genes, such as XIAP, survivin, Bcl-xL and Bcl-2, in breast cancer cells and breast tumor xenograft. Reduced Ki67 and increased TUNEL staining were observed in TQ-treated tumors. TQ was also found to increase the level of catalase, superoxide dismutase and glutathione in mouse liver tissues.”

Again we see increases in the profoundly important glutatione under the influence of thymoquinone. Note also that the antitumor effect of the conventional chemotherapeutic agent was enhanced.

“In conclusion, our study provides evidence for the mechanism of action of TQ in suppressing human breast carcinoma in both in vitro and in vivo models. We demonstrated that the anti-proliferative and pro-apoptotic effects of TQ are mediated through its induction effect on p38 and ROS signaling. Our results also indicate the anti-tumor effects of TQ in breast tumor xenograft mice and its ability to potentiate the antitumor effect of doxorubicin. TQ serves as a promising anticancer agent and further studies may provide important leads for its clinical application.”

Journal of Medicinal FoodA study published in the Journal of Medicinal Food also reports proapoptotic and antimetastatic effects of Nigella sativa for breast cancer:

“This study investigated the apoptotic, antimetastatic, and anticancer activities of supercritical carbon dioxide (SC-CO2) extracts of the seeds of N. sativa Linn. against estrogen-dependent human breast cancer cells (MCF-7)….Of the 12 extracts, 1 extract (A3) that was prepared at 60°C and 2500 psi (~17.24 MPa) showed selective antiproliferative activity against MCF-7 cells with an IC50 of 53.34±2.15 μg/mL. Induction of apoptosis was confirmed by evaluating caspases activities and observing the cells under a scanning electron microscope. In vitro antimetastatic properties of A3 were investigated by colony formation, cell migration, and cell invasion assays. The elevated levels of caspases in A3 treated MCF-7 cells suggest that A3 is proapoptotic. Further nuclear condensation and fragmentation studies confirmed that A3 induces cytotoxicity through the apoptosis pathway. A3 also demonstrated remarkable inhibition in migration and invasion assays of MCF-7 cells at subcytotoxic concentrations. Thus, this study highlights the therapeutic potentials of SC-CO2 extract of N. sativa in targeting breast cancer.”

Pharmacognosy ResearchAnd authors of a study published in Pharmacognosy Research also report activity of thymoquinone against breast cancer:

“The study addressed the anti-cancer efficiency of long-term in vitro treatment with thymoquinone towards human breast cancer cell lines MCF-7...The 50% inhibitory concentration (IC50) value determined using the proliferation assay was 25 μM thymoquinone. Late apoptotic cell percentage increased rapidly when treatment duration was increased to 24 h with 25 and 100 μM thymoquinone. Further analysis using cell cycle assay showed thymoquinone inhibition of breast cancer cell proliferation at minimal dose 25 μM and led to S phase arrest significantly at 72 h treatment. It was also noted elevation sub-G1 peak following treatment with 25 μM thymoquinone for 12 h. Increase in thymoquinone to 50 μM caused G2 phase arrest at each time-point studied…In general thymoquinone showed sustained inhibition of breast cancer cell proliferation with long-term treatment. Specificity of phase arrest was determined by thymoquinone dose.”

Asian Pacific Journal of Cancer PreventionAntiproliferative effects against breast cancer cells were also shown in a study published in the Asian Pacific Journal of Cancer Prevention:

“Our data showed that Nigella sativa extracts significantly inhibited human breast cancer MDA-MB-231 cell proliferation at doses of 2.5-5 μg/mL. Apoptotic induction in MDA-MB-231 cells was observed in a dose-dependent manner after exposure to Nigella sativa extracts for 48 h. Real time PCR and flow cytometry analyses suggested that Nigella sativa extracts possess the ability to suppress the proliferation of human breast cancer cells through induction of apoptosis.”

Nigella sativa protects against liver damage caused by tamoxifen

Canadian Journal of Physiology and PharmacologyProtection against the harmful toxic effects of chemotherapy is a critical component of cancer case management. A welcome study published in the Canadian Journal of Physiology and Pharmacology shows that thymoquinone from Nigella sativa protects against the hepatotoxicity of tamoxifen:

“One of the major reasons for terminating a clinical trial is the liver toxicity induced by chemotherapy. Tamoxifen (TAM) is an anti-estrogen used in the treatment and prevention of hormone-dependent breast cancer. Tamoxifen therapy may cause hepatic injury. The seeds of Nigella sativa, which contain the active ingredient thymoquinone (TQ), have been used in folk medicine for diverse ailments. TQ is reported to possess anticancer and hepatoprotective effects. In this study, the protective effects of TQ against TAM-induced hepatotoxicity in female rats were evaluated. Four groups of rats were used: control; TAM; TQ; TAM+TQ. TAM (45 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection (i.p.), for 10 consecutive days) resulted in elevated serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, and gamma glutamyl transferase, as well as depletion of reduced glutathione in the liver and accumulation of lipid peroxides. Also, TAM treatment inhibited the hepatic activity of superoxide dismutase. Further, it raised the levels of tumor necrosis factor alpha in the liver and induced histopathological changes. Pretreatment with TQ (50 mg·(kg body mass)(-1)·day(-1); orally, for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. TQ significantly inhibited TAM-induced hepatic GSH depletion and LPO accumulation. Consistently, TQ normalized the activity of SOD, inhibited the rise in TNF-α and ameliorated the histopathological changes. In conclusion, TQ protects against TAM-induced hepatotoxicity.”

Again we see beneficial effects on glutatione metabolism.

Protection against kidney toxicity of cisplatin

Iranian Journal of Kidney DiseasesWhile on the topic of protection unwanted against damage done by cytotoxic chemotherapy, we can appreciate a study published in the Iranian Journal of Kidney Diseases reporting evidence that Nigella sativa offers some protection against the nephrotoxic effects of cisplatin:

“Thirty rats were divided into 3 groups to receive distilled water (control group), cisplatin (3 mg/kg per body weight for 3 days), and cisplatin and alcoholic extract of NS (100 mg/kg per body weight). Biochemical and histopathologic parameters were compared between the three groups on days 14 and 42 of the study…Cisplatin-induced nephrotoxicity was confirmed in our study…Histology of the kidneys exposed to cisplatin showed significant kidney injury, but the rats treated with NS showed a relatively well-preserved architectureNigella sativa seeds had nonsignificant effects on biochemical parameters, although the histopathologic properties of the kidneys relatively recovered after NS use.”

Nigella sativa benefits for the brain, mood and cognition

Journal of EthnopharmacologyConsidering the immune-regulating and anti-inflammatory virtues of Nigella sativa it stands to reason that there would be benefits for the brain. A study published in the Journal of Ethnopharmacology reports that it helps stabilize mood, reduce anxiety and cognition in adolescent males.

“Previous studies conducted on animals linked consumption of Nigella sativa L. seeds (NS) to decreased anxiety and improved memory. The present study, which was carried out at a boarding school in Bangladesh, was designed to examine probable effect of NS on mood, anxiety and cognition in adolescent human males…Forty-eight healthy adolescent human males aged between 14 to 17 years were randomly recruited as volunteers and were randomly split into two groups: A (n=24) and B (n=24). The treatment procedure for group A and B were one capsule of 500 mg placebo and 500 mg NS respectively once daily for four weeks. All the volunteers were assessed for cognition with modified California verbal learning test-II (CVLT-II), mood with Bond–Lader scale and anxiety with State–Trait Anxiety Inventory (STAI) at the beginning and after four weeks of either NS or placebo ingestion…Over the 4 weeks study period, the use of NS as a nutritional supplement been observed to- stabilize mood, decrease anxiety and modulate cognition positively.”

Relieving neuroinflammation of depression

Journal of Pharmacy & BioAllied SciencesIt’s well known than neuroimmune inflammation plays a fundamental role in depression. Authors of a study published in the Journal of Pharmacy & BioAllied Sciences present welcome evidence that Nigella sativa and thymoquinone may relieve depression by reducing neuroinflammation:

Neuroimmune factors have been proposed as contributors to the pathogenesis of depression. Beside other therapeutic effects including neuroprotective, antioxidant, anticonvulsant and analgesic effects, Nigella sativa and its main ingredient, thymoquinone (TQ), have been shown to have anti-inflammatory effects. In the present study, the effects of Nigella sativa hydro-alcoholic extract and thymoquinone was investigated on lipopolysaccharide- induced depression like behavior in rats…The results of the present study showed that hydro-alcoholic extract of Nigella sativa can prevent LPS-induced depression like behavior in rats. These results support the traditional belief on the beneficial effects of Nigella sativa in the nervous system.”

Thymoquinone ameliorates lead-induced brain damage

Experimental and Toxicologic PathologyEnvironmental toxicity is a concern for brain health; an exciting study published Experimental and Toxicologic Pathology indicates that thymoquinone from Nigella sativa protects against brain damage from lead:

“The present study aims to investigate the protective effects of thymoquinone, the major active ingredient of Nigella sativa seeds, against lead-induced brain damage in Sprague-Dawley rats. In which, 40 rats were divided into four groups (10 rats each). The first group served as control. The second, third and fourth groups received lead acetate, lead acetate and thymoquinone, and thymoquinone only, respectively, for one month. Lead acetate was given in drinking water at a concentration of 0.5 g/l (500 ppm). Thymoquinone was given daily at a dose of 20 mg/kg b.w. in corn oil by gastric tube. Control and thymoquinone-treated rats showed normal brain histology. Treatment of rats with lead acetate was shown to produce degeneration of endothelial lining of brain blood vessels with peri-vascular cuffing of mononuclear cells consistent to lymphocytes, congestion of choroid plexus blood vessels, ischemic brain infarction, chromatolysis and neuronal degeneration, microglial reaction and neuronophagia, degeneration of hippocampal and cerebellar neurons, and axonal demyelination. On the other hand, co-administration of thymoquinone with lead acetate markedly decreased the incidence of lead acetate-induced pathological lesions.”

Protection against Parkinson’s disease α-synuclein-induced synapse damage

Neuroscience LettersAgents that offer protection against α-synuclein toxicity are welcome in the treatment of Parkinson’s disease and dementia. A study recently published in Neuroscience Letters presents evidence that thymoquinone from Nigella sativa has this property:

“The present study aimed to determine whether TQ protects against α-synuclein (αSN)-induced synaptic toxicity in rat hippocampal and human induced pluripotent stem cell (hiPSC)-derived neurons. Here, we report that αSN decreased the level of synaptophysin, a protein used as an indicator of synaptic density, in cultured hippocampal and hiPSC-derived neurons. However, simultaneous treatment with αSN and TQ protected neurons against αSN-induced synapse damage, as revealed by immunostaining. Moreover, administration of TQ efficiently induced protection in these cells against αSN-induced inhibition of synaptic vesicle recycling in hippocampal and hiPSC-derived neurons as well as against mutated P123H β-synuclein (βSN) in hippocampal neurons, as revealed by experiments using the fluorescent dye FM1-43. Using a multielectrode array, we further demonstrated that the treatment of hiPSC-derived neurons with αSN induced a reduction in spontaneous firing activity, and cotreatment with αSN and TQ partially reversed this loss. These results suggest that TQ protects cultured rat primary hippocampal and hiPSC-derived neurons against αSN-induced synaptic toxicity and could be a promising therapeutic agent for patients with Parkinson’s disease and dementia with Lewy bodies.

Thymoquinone prevents β-amyloid neurotoxicity of Alzheimer’s disease

Cellular and Molecular NeurobiologyOf great interest in the prevention of Alzheimer’s disease are agents that may protect agains β-amyloid neurotoxicity. Here too thymoquinone has effect as reported in a study published in Cellular and Molecular Neurobiology:

Thymoquinone (TQ), a bioactive constituent of Nigella sativa Linn (N. sativa) has demonstrated several neuropharmacological attributes. In the present study, the neuroprotective properties of TQ were investigated by studying its anti-apoptotic potential to diminish β-amyloid peptide 1-40 sequence (Aβ1-40)-induced neuronal cell death in primary cultured cerebellar granule neurons (CGNs)…Pretreatment of CGNs with TQ (0.1 and 1 μM) and subsequent exposure to 10 μM Aβ1-40 protected the CGNs against the neurotoxic effects of the latter. In addition, the CGNs were better preserved with intact cell bodies, extensive neurite networks, a loss of condensed chromatin and less free radical generation than those exposed to Aβ1-40 alone. TQ pretreatment inhibited Aβ1-40-induced apoptosis of CGNs via both extrinsic and intrinsic caspase pathways. Thus, the findings of this study suggest that TQ may prevent neurotoxicity and Aβ1-40-induced apoptosis. TQ is, therefore, worth studying further for its potential to reduce the risks of developing Alzheimer’s disease.”

 Nigella sativa protects and promotes healing from nerve trauma

Pathologie BiologieA study published Pathologie Biologie reports that Nigella sativa improves the neurodegeneration typical after nerve trauma:

“The aim of this study was designed to evaluate the possible protective effects of Nigella sativa (NS) on the neuronal injury in the sciatic nerve of rats. The rats were randomly allotted into one of the three experimental groups: A (control), B (only trauma) and C (trauma and treated with NS); each group contain 10 animals… To date, no histopathological changes of neurodegeneration in the sciatic nerve after trauma in rats by NS treatment have been reported. Results showed in the group B (only trauma), the neurons of sciatic nerve tissue became extensively dark and degenerated with picnotic nuclei. Treatment of NS markedly reduced degenerating neurons after trauma and the distorted nerve cells were mainly absent in the NS-treated rats. The morphology of neurons in groups treated with NS was well protected, but not as neurons of the control group. The number of neurons in sciatic nerve tissue of group B (only trauma) was significantly less than both control and treated with NS groups. The morphology of neurons revealed that the number of neurons were significantly less in group B compared to control and group C rats’ motor neurons anterior horn spinal cord tissue. We conclude that NS therapy causes morphologic improvement on neurodegeneration in sciatic nerve after trauma in rats.”

Nigella sativa for osteoporosis

Evidence-Based Complementary and Alternative MedicineConsidering that inflammation plays a key role in osteoporosis, it’s reasonable to investigate the use Nigella sativa as described in a paper in Evidence-Based Complementary and Alternative Medicine:

“Animal studies have shown that NS and TQ may be used for the treatment of diabetes-induced osteoporosis and for the promotion of fracture healing. The mechanism involved is unclear, but it was postulated that the antioxidative, and anti-inflammatory activities may play some roles in the treatment of osteoporosis as this bone disease has been linked to oxidative stress and inflammation. This paper highlights studies on the antiosteoporotic effects of NS and TQ, the mechanisms behind these effects and their safety profiles. NS and TQ were shown to inhibit inflammatory cytokines such as interleukin-1 and 6 and the transcription factor, nuclear factor κB. NS and TQ were found to be safe at the current dosage for supplementation in human with precautions in children and pregnant women. Both NS and TQ have shown potential as antiosteoporotic agent but more animal and clinical studies are required to further assess their antiosteoporotic efficacies.”

Inhibition of osteoporosis by Nigella sativa

BMC Complementary & Alternative MedicineIn an exciting study published in the BMC Complementary and Alternative Medicine, investigators report the reversal of osteoporosis in subjects whose ovaries had been removed:

“There is a direct relationship between the lack of estrogen after menopause and the development of osteoporosis…Nigella Sativa (NS) has been shown to have beneficial effects on bone and joint diseases. The present study was conducted to elucidate the protective effect of Nigella Sativa on osteoporosis produced by ovariectomy in rats…Female Wistar rats aged 12-14 months were divided into three groups: sham-operated control (SHAM), ovariectomized (OVX), and ovariectomized supplemented with nigella sativa (OVX-NS) orally for 12 weeks; 4 weeks before ovariectomy and 8 weeks after…OVX rats showed significant decrease in plasma Ca(+2), accompanied by a significant increase in plasma ALP, amino terminal collagen type 1 telopeptide, MDA, nitrates, TNF-α and IL-6. These changes were reversed by NS supplementation in OVX-NS group to be near SHAM levels. Histological examination of the tibias revealed discontinuous eroded bone trabeculae with widened bone marrow spaces in OVX rats accompanied by a significant decrease in both cortical and trabecular bone thickness compared to Sham rats. These parameters were markedly reversed in OVX-NS rats. Histological examination of the liver showed mononuclear cellular infiltration and congestion of blood vessels at the portal area in OVX rats which were not found in OVX-NS rats.”

Their data supported this exciting conclusion:

“It can be concluded that NS has shown potential as a safe and effective antiosteoporotic agent, which can be attributed to its high content of unsaturated fatty acids as well as its antioxidant and anti-inflammatory properties.”

Nigella sativa helps with psoriasis

Pharmacognosy MagazineConsidering its antiinflammatory and immunomodulating characteristics it seems a good bet that Nigella sativa would help with psoriasis as described in a study published in Pharmacognosy Magazine:

“The screening of antipsoriatic activity of 95% of ethanolic extract of Nigella sativa seeds by using mouse tail model for psoriasis and in vitro antipsoriatic activity was carried out by SRB Assay using HaCaT human keratinocyte cell lines….The ethanolic extract of Nigella sativa seeds extract produced a significant epidermal differentiation, from its degree of orthokeratosis (71.36±2.64) when compared to the negative control (17.30±4.09%)…The 95% ethanolic extract of Nigella sativa shown IC50 239 μg/ml, with good antiproliferant activity compared to Asiaticoside as positive control which showed potent activity with IC50 value of 20.13 μg/ml. From the present study it can be said that topical application of 95% ethanolic extract of Nigella sativa seeds has antipsoriatic activity and the external application is be beneficial in the management of psoriasis.”

Assists in treatment of vitiligo

Iranian Red Crescent Medical JournalNIgella sativa is an agent to consider in case management of any autoimmune disorder including vitiligo, for which it showed benefit in a study published in the Iranian Red Crescent Medical Journal:

Vitiligo is one of the autoimmune skin diseases that destroy the melanocytes of the skin…The aim of this study was to compare the effect of Nigella sativa and fish oil on vitiligo lesions of the patients referred to a dermatology clinic…After six months, a mean score of VASI decreased from 4.98 to 3.75 in patients applying topical Nigella sativa and from 4.98 to 4.62 in those using topical fish oil…In the current study, administration of Nigella sativa and fish oil significantly decreased skin lesions size, indicating an improvement in clinical condition…the depigmented areas were reduced over time and the skin color showed improvement. One reason for this positive response to treatment is the thymoquinone component of Nigella sativa…Thymoquinone can simulate the activity of acetylcholine, which causes the release of melanin and darkening of the skin through stimulation of cholinergic receptors. In addition, Nigella sativa oil administration was tolerable as well as safe and improved oxidative stress and clinical condition of patients…It was also shown that this type of treatment has no significant side effects and resulted in high patient satisfaction and acceptance.”

The authors state in conclusion:

“Nigella sativa oil and fish oil were effective in reduction the size of patient’s lesions; however, Nigella sativa was more effective in comparison to the fish oil. Therefore, using Nigella sativa with the major drugs in the treatment of vitiligo is recommended.”

Topical treatment of allergic rhinitis

Anti-Inflammatory & Anti-Allergy Agents in Medicinal ChemistryAllergic rhinitis as a chronic inflammatory disorder also responds to Nigella sativa applied topically as reported in Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry:

Allergic rhinitis (AR) is the most common manifestation of atopic reaction to inhaled allergens. It is a chronic inflammatory disease which may first appear at any age, but the onset is usually during childhood or adolescence…The individuals in the active group received N. sativa oil and the control group individuals received ordinary food oil in the form of nasal drops for 6 weeks…After the 6 weeks treatment course, 100% of the patients in the mild active group became symptoms free; while in moderate active group 68.7% became symptoms free and 25% were improved; while in severe active group 58.3% became symptoms free and 25% were improved. In addition, 92.1% of total patients in the active group demonstrated improvement in their symptoms or were symptoms free, while the corresponding value was 30.1% in the control group. At the end of 6 weeks of treatment with topical use, the improvement in tolerability of allergen exposure in active group became 55.2% which was significant as compared with control group which was accounted for 20% at the same time…Topical application of black seed oil was effective in the treatment of allergic rhinitis, with minimal side effects.”

Nigella sativa protects against radiation damage

Journal of Investigative SurgeryRadiation therapy can produce substantial ‘collateral damage’. Authors of a study just published in the Journal of Investigative Surgery demonstrate that Nigella sativa reduces oxidative stress in animals subjected to total head irradiation:

“Many cancer patients treated with radiotherapy suffer severe side effects during and after their treatment. The aim of this study was to investigate the effects of irradiation and the addition of Nigella sativa oil (NSO) on the oxidant/antioxidant system in the liver tissue of irradiated rats…The control group received neither NSO nor irradiation but received 1-ml saline orally. The irradiation group (IR) received total head 5 gray (Gy) of gamma irradiation as a single dose, plus 1-ml saline orally. The IR plus NSO group received both total head 5 Gy of gamma irradiation as a single dose and 1 g/kg/day NSO orally through an orogastric tube starting one hour before irradiation and continuing for 10 days…Conclusions: NSO reduces oxidative stress markers and has antioxidant effects, which also augments the antioxidant capacity in the liver tissue of rats.”

Cutaneous and Ocular ToxicologyNigella sativa was shown to reduce radiation-induced cataracts in a study published in Cutaneous and Ocular Toxicology:

“The aim of this study was to investigate the antioxidant and radioprotective effects of Nigella sativa oil (NSO) and thymoquinone (TQ) against ionizing radiation-induced cataracts in lens after total cranium irradiation (IR) of rats with a single dose of 5 gray (Gy)…At the end of the 10th d, cataract developed in 80% of the rats in IR group only. After IR, cataract rate dropped to 20% and 50% in groups which were treated with NSO and TQ, respectively, and was limited at grades 1 and 2. Nitric oxide synthase activity, nitric oxide and peroxynitrite levels in the radiotherapy group were higher than those of all other groups. Conclusions: The results implicate a major role for NSO and TQ in preventing cataractogenesis in ionizing radiation-induced cataracts in the lenses of rats, wherein NSO were found to be more potent.”

PhytomedicineAnd protection from radiation-induced damage to brain tissue was demonstrated in a study recently published in the journal Phytomedicine designed…

“To investigate Nigella sativa oil (NSO) and Thymoquinone (TQ) for their antioxidant effects on the brain tissue of rats exposed to ionizing radiation….Levels of NO· and ONOO(-), and enzyme activity of NOS in brain tissue of the rats treated with NSO or TQ were found to be lower than in received IR alone (p<0.002) Nigella sativa oil (NSO) and its active component, TQ, clearly protect brain tissue from radiation-induced nitrosative stress.

 Activity against Staphylococcal and fungal skin infections

Pakistan Journal of Biological SciencesNigella sativa is a benevolent agent in the treatment of skin infection and inflammation as documented by a study published in the Pakistan Journal of Biological Sciences:

“Nigella sativa has been used for a long time in Jordanian folk medicine to treat skin diseases like microbial infections and inflammation. Therefore, the present study was conducted to assess the healing efficacy of petroleum ether extract of Nigella sativa seeds (fixed oil) on staphylococcal-infected skin. Male BALB/c mice were infected with 100 microL of Staphylococcus aureus (ATCC 6538)… Application of treatments for each group (100 microL sterile saline, 100 microL chloramphenicol (10 microg/mouse) and Nigella sativa fixed oil at a dose of 50, 100 or 150 microL/mouse) was performed at the site of infection… At day 3 and 5 after infection, total White Blood Cells (WBCs) count; differential and absolute differential WBC counts and the number of viable bacteria present in the skin area were measured…Results indicated that fixed oil of Nigella sativa seeds enhance healing of staphylococcal-infected skin by reducing total and absolute differential WBC counts, local infection and inflammation, bacterial expansion and tissue impairment. These effects provide scientific basis for the use of Nigella sativa in traditional medicine to treat skin infections and inflammations.

Journal of EthnopharmacologyThe authors of a study published in the Journal of Ethnopharmacology report effectiveness against fungal skin infections (dermatophytes):

“The antifungal activity of ether extract of Nigella sativa seed and its active principle thymoquinone was tested against eight species of dermatophytes: four species of Trichophyton rubrum and one each of Trichophyton interdigitale, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. Agar diffusion method with serial dilutions of ether extract of Nigella sativa, thymoquinone and griseofulvin was employed…The minimum inhibitory concentration (MIC) was considered as the minimum concentration of the drug, which inhibited 80–100% of the fungal growth. The MICs of the ether extract of Nigella sativa and thymoquinone were between 10 and 40 and 0.125 and 0.25 mg/ml…These results denote the potentiality of Nigella sativa as a source for antidermatophyte drugs and support its use in folk medicine for the treatment of fungal skin infections.”

Case report of seroreversion in HIV

Afr J Tradit Complement Altern Med.A case report published in the African Journal of Traditional, Complementary, and Alternative Medicines presents unexpected results in the treatment of HIV:

“Nigella sativa had been documented to possess many therapeutic functions in medicine but the least expected is sero-reversion in HIV infection which is very rare despite extensive therapy with highly active anti-retroviral therapy (HAART). This case presentation is to highlight the complete recovery and sero-reversion of adult HIV patient after treatment with Nigella sativa concoction for the period of six months. The patient presented to the herbal therapist with history of chronic fever, diarrhoea, weight loss and multiple papular pruritic lesions of 3 months duration. Examination revealed moderate weight loss, and the laboratory tests of ELISA (Genscreen) and western blot (new blot 1 & 2) confirmed sero-positivity to HIV infection with pre-treatment viral (HIV-RNA) load and CD4 count of 27,000 copies/ml and CD4 count of 250 cells/ mm(3) respectively. The patient was commenced on Nigella sativa concoction 10 mls twice daily for 6 months. He was contacted daily to monitor side-effects and drug efficacy. Fever, diarrhoea and multiple pruritic lesions disappeared on 5th, 7th and 20th day respectively on Nigella sativa therapy. The CD4 count decreased to 160 cells/ mm3 despite significant reduction in viral load (≤1000 copies/ml) on 30th day on N. sativa. Repeated EIA and Western blot tests on 187th day on Nigella sativa therapy was sero-negative. The post therapy CD4 count was 650 cells/ mm(3) with undetectable viral (HIV-RNA) load. Several repeats of the HIV tests remained sero-negative, aviraemia and normal CD4 count since 24 months without herbal therapy. This case report reflects the fact that there are possible therapeutic agents in Nigella sativa that may effectively control HIV infection.

Improvement in semen quality

PhytomedicineAnother study published in Phytomedicine presents evidence from a double-blind, placebo-controlled that Nigella sativa improves abnormal semen quality in infertility:

“Since Nigella sativa L. seed (N. sativa) has many uses including infertility in traditional medicine, the effects of Nigella sativa L. seed oil on abnormal semen quality in infertile men with abnormal semen quality are of interest. This study was conducted on Iranian infertile men with inclusion criteria of abnormal sperm morphology less than 30% or sperm counts below 20×10(6)/ml or type A and B motility less than 25% and 50% respectively. The patients in N. sativa oil group (n=34) received 2.5mlN. sativa oil and placebo group (n=34) received 2.5ml liquid paraffin two times a day orally for 2 months. At baseline and after 2 months, the sperm count, motility and morphology and semen volume, pH and round cells as primary outcomes were determined in both groups. Results showed that sperm count, motility and morphology and semen volume, pH and round cells were improved significantly in N. sativa oil treated group compared with placebo group after 2 months. It is concluded that daily intake of 5ml N. sativa oil for two months improves abnormal semen quality in infertile men without any adverse effects.”

Is Nigella sativa safe?

Advanced Pharmaceutical BulletinA study investigating the potential for liver toxicity was reported last year in the journal Advanced Pharmaceutical Bulletin:

“The aim of this study was to determine the toxic effect of Nigella sativa powder on the liver function which was evaluated by measuring liver enzymes and through histopathological examination of liver tissue…Twenty four male Sprague Dawley rats were allotted randomly to four groups including: control (taking normal diet); low dose (supplemented with 0.01 g/kg/day Nigella sativa); normal dose (supplemented with 0.1 g/kg/day Nigella sativa) and high dose (supplemented with 1 g/kg/day Nigella sativa)…To assess liver toxicity, liver enzymes measurement and histological study were done at the end of supplementation…The study showed that supplementation of Nigella sativa up to the dose of 1 g/kg supplemented for a period of 28 days resulted no changes in liver enzymes level and did not cause any toxicity effect on the liver function

The authors stated this conclusion regarding human consumption of Nigella sativa:

“With the evidence of normal ALT and AST level in blood and normal liver tissue in histology examination for all treatment groups, it is suggested that there are no toxic effect on liver function of Nigella sativa at different doses for 4 weeks period. As a conclusion, popular consumption of Nigella sativa powder by human did not cause any toxicity effect on the liver function and safe to be consumed for many purposes.”

 Protection against alcohol-induced liver injury

Chinese Journal of Natural MedicinesNot only is Nigella sativa safe for the liver, but a study published in the Chinese Journal of Natural Medicines provides data showing that it protects the liver against oxidative damage caused by alcohol:

Nigella sativa L. (Ranunculaceae) is considered as a therapeutic plant-based medicine for liver damage. In this study, the aim was to study the effect of Nigella sativa oil (NSO) pretreatment on ethanol-induced hepatotoxicity in rats…Rats were given Nigella sativa oil at doses of 2.5 and 5.0 mL·kg(-1), orally for 3 weeks, followed by oral ethanol (EtOH) administration (5 g·kg(-1)) every 12 h three times (binge model).”

Amazingly…

Binge ethanol application caused significant increases in plasma transaminase activities and hepatic triglyceride and malondialdehyde (MDA) levels. It decreased hepatic glutathione (GSH) levels, but did not change vitamins E and vitamin C levels and antioxidant enzyme activities. NSO (5.0 mL·kg(-1)) pretreatment significantly decreased plasma transaminase activities, hepatic MDA, and triglyceride levels together with amelioration in hepatic histopathological findings.”

Based on these findings the authors conclude:

“NSO pretreatment may be effective in protecting oxidative stress-induced hepatotoxicity after ethanol administration.”

Practical use of Nigella sativa

Nigella sativa seeds 3The foregoing sampling of studies from the scientific literature on Nigella sativa should not be construed as an endorsement for its use in any specific case or condition. It is a presentation of the extraordinary scope of action and clinical potential of an agent that I am finding valuable in practice. Colleagues who are interested in knowing the particular Nigella sativa whole seed extract that I am using are welcome to contact me. For the general reader, I caution against taking anything (especially something found on the internet) without having first discussed it with your knowledgeable health care practitioner who has the background and depth to advise on how this may fit into your treatment or health maintenance plan.

Depression, dementia and brain glucose

Psychiatry Research- NeuroimagingDepression and dementia, including Alzheimer’s disease, are strongly affected by brain glucose and insulin regulation. A study just published in the journal Psychiatry Research: Neuroimaging presents evidence that brain glucose dysregulation is a modifiable risk factor for both depression and dementia/Alzheimer’s disease in later life. The authors state:

“Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer’s disease (AD)…Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD.”

Furthermore…

“Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD.”

So they correlated fasting serum glucose (FSG) levels in non-diabetic young (YC) and elderly controls (EC) and late-life depression patients with PET scans of cerebral glucose metabolism. There was indeed an association of brain dysglycemia with depression and dementia:

“The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions.”

In other words, increased serum glucose with cerebral insulin resistance (hence decreased brain glucose metabolism) correlated with both depression and cognitive deficits. The authors conclude:

“Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk.”

See earlier posts on insulin resistance, dysglycemia (glucose dysregulation), HgbA1c and brain health.

Bipolar disorder and neuroinflammation

Journal of NeuroinflammationBipolar disorder, like a host of other psychiatric illnesses, should be assessed for neuroinflammation and its underlying causes as evidenced by a wealth of recently published studies. The authors of a paper recently published in the Journal of Neuroinflammation state:

“Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders).”

Or great practical clinical significance…

“As biological abnormalities are increasingly identified among patients with psychiatric disorders, the distinction between neurological and psychiatric illness fades. In addition to systemic autoimmune diseases associated with psychiatric manifestations (for example, lupus), more recently, patients with acute isolated psychosis were identified with synaptic autoimmune encephalitides. These patients are often erroneously diagnosed with refractory primary psychotic disorders, delaying initiation of effective immune therapy. Additionally, growing evidence supports the pathogenic role of anti-neuronal antibodies in neuropsychiatric disorders.”

The authors undertake a review of the extensive literature documenting the role of common autoimmune disorders, autoimmune encephalitides associated with serum anti-synaptic and glutamic acid decarboxylase autoantibodies, anti-basal ganglia/thalamic autoantibodies, and innate inflammation with glial pathology, elevated cytokines levels, cyclooxygenase activation, glutamate dysregulation, increased S100B levels, increased oxidative stress, and blood brain barrier (BBB) dysfunction in bipolar disorder and other neuropsychiatric illnesses.

Regarding the use of antiinflammatory agents in the treatment of psychiatric disorders they state:

“Several human and animal studies suggest that certain antiinflammatory drugs may play an important adjunctive role in the treatment of psychiatric disorders…Although current immune therapies (for example, IVIG, plasmapheresis, corticosteroids and immunosuppressive agents) are often effective for treating autoimmune encephalitides wherein inflammation is acute, intense and predominately of adaptive origin, their efficacy in classical psychiatric disorders wherein inflammation is chronic, much milder, and predominately of innate origin, is limited. Development of novel therapeutics should aim at reversing glial loss, down-regulating harmful MAP [microglial activation and proliferation], while optimizing endogenous neuroprotective T regs and beneficial MAP, rather than indiscriminately suppressing inflammation as occurs with current immunosuppressive agents. Additionally, development of potent co-adjuvant antioxidants that would reverse oxidative injury in psychiatric disorders is needed.”

 

Current Psychiatry ReportsIn reference to bipolar disorder specifically the authors of a paper published in Current Psychiatry Reports state:

Bipolar disorder is now known to be associated not only with highly prevalent co-occurring psychiatric and substance use disorders but also with medical comorbidities, such as cardiovascular diseases, diabetes mellitus, obesity and thyroid dysfunction. Inflammatory disturbances repeatedly observed in bipolar disorder, can explain some of the comorbidity between bipolar disorder and medical disorder. This revised perspective of bipolar disorders should promote the development of therapeutic tools.”

In particular…

Immuno-inflammatory dysfunction may well represent a significant component of the underlying pathophysiology of the disorder. We therefore propose to review the immuno-inflammatory hypothesis in bipolar disorder considering the co-occurence with autoimmune diseases, immunological and inflammatory markers, as well as immuno-genetic markers which could lead to personalized treatments.”

 

Australian & New Zealand Journal of PsychiatryA recent paper in the Australian & New Zealand Journal of Psychiatry strikes a similar chord and highlights the role of autoimmunity:

“Increasing evidence suggests that inflammation and immune dysregulation play an important role in the pathogenesis of bipolar disorder. Because the brain can be affected by various autoimmune processes, it is possible that some psychiatric disorders may have an autoimmune basis.”

In review of the literature on peripheral and central immune dysregulation and autoimmunity in bipolar disorder they note, in addition to the mechanisms described above, association with common autoimmune conditions such as SLE and autoimmune thyroiditis:

Neuroinflammation and peripheral immune dysregulation may play a role in the pathophysiology of bipolar disorder. This involves a complex interaction between immune cells of the central nervous system and periphery resulting in cellular damage through mechanisms involving excitotoxicity, oxidative stress, and mitochondrial dysfunction. Neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are important differentials for a psychiatrist to consider when suspecting autoimmune encephalopathy.”

The authors conclude:

The link between immune dysregulation, autoimmunity, and bipolar disorder may be closer than previously thought. Psychiatrists should be vigilant for autoimmunity in presentations of bipolar disorder due to its high morbidity and therapeutic implications. Advances in neuroimaging and biomarker identification related to immune dysregulation and neuroinflammation will contribute to our knowledge of the pathophysiology of bipolar disorder.”

 

Journal of Affective DisordersIn a paper published in the Journal of Affective Disorders, the authors examine the incidence of comorbid medical disorders and present evidence that…

“…bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.”

They dispense with the notion that comorbid medical disorders are entirely due to the deleterious effects of psychotropic medications:

“Until recently, a lot of emphasis has been put on the fact that psychotropic medication contributes to cardiovascular risk factors. Lithium can cause weight gain and adversely influence glucose metabolism, valproic acid is associated to weight gain and insulin resistance, second generation anti-psychotics are associated to hyperlipidemia, increased risk with diabetes, and weight gain though the extent of weight gain depends on which antipsychotic is used. It should however be stressed that the increased mortality rate in bipolar predate modern pharmacologic treatments. In addition, the fact that the association between cardiovascular risk factors and bipolar disorder remains significant after controlling for these co-factors strongly suggests that mechanisms specific to bipolar disorder itself have yet to be identified.”

And in fact inflammation is common to both:

“Inflammation has been shown to be crucial throughout atherosclerosis from endothelial dysfunction to plaque rupture and thrombosis; a number of studies also suggest that inflammation may be implicated in the pathophysiology of bipolar disorder (for review see, Goldstein et al., 2009). The data supporting the hypothesis that inflammation could be a common factor underlying both cardio-vascular and bipolar disorder is important to be reviewed.”

Bipolar disorder and abnormal immuno-inflammationMoreover…

“Over the last two decades, it has been shown that inflammatory processes and neural immune interactions are involved in the pathophysiology of major depression, these data also shed light on how to explain the plausible link between increased levels of cytokines and mood states in bipolar disorder. A pro-inflammatory state is known to activate the tryptophan and serotonin-degrading-enzyme, indoleamine 2–3 dioxygenase (IDO), which has been found elevated in the plasma of bipolar patients. Activation of this enzyme leads to increased consumption of tryptophan, thus reducing the availability of serotonergic neurotransmission, as well as inducing the production of detrimental tryptophan catabolites with neurotoxic effects. It has also been shown that the activity of dopaminergic system is reduced in response to inflammation while cytokines enhance the re-uptake of monoamine neuro-transmitters thereby reducing their intra-synaptic concentrations in the brain.”

BDNF (brain derived neurotrophic factor) regulation is also disrupted:

“The pro-inflammatory cytokines also induce decrease in neurotrophins, and in particular diminished levels of Brain-Derived-Neurotrophic-Factor (BDNF) leading to decrease neuronal repair, decrease in neurogenesis and an increased activation in glutamatergic pathway which also contributes to neuronal apoptosis. It is noteworthy that serum BDNF has been associated both with changes in mood states in bipolar disorder as well as in coronary heart diseases.”

The autoimmune component is of premiere importance:

“A relationship between auto-immune disorders and bipolar disorder has been reported as early as 1888. Patients with bipolar disorder tend to develop organ-specific autoimmunity as shown, for example, by thyro-peroxidase antibodies (TPO-Abs) associated with thyroid failure, by antibodies to H/KAT-Pase associated with atrophic gastritis and by GAD65A, isoform of glutamic acid decarboxylase which is a marker of type-I diabetes. Recently, manic episodes with psychotic symptoms were observed during acute encephalitis with antibodies directed in particular against extracellular domains of the glutamatergic NMDA receptor. In addition, it has recently been reported that gastrointestinal processing of food antigens such as bovine caseins and wheat glutens is altered in bipolar disorder. Bipolar patients have been reported to have increased antibodies to gliadin, a glycoprotein derived from the ingestion of gluten from wheat or to casein activation, particularly during mania…Presence of these auto-antibodies might even precede the onset of bipolar disorder, as an increased prevalence of Multiple Sclerosis, thyrotoxicosis, ulcerative colitis, psoriasis and rheumatoid arthritis has been reported in unaffected relatives of patients with BD.”

 

Current Opinion in PsychiatryThe authors of a paper just published in Current Opinion in Psychiatry note:

“Recent studies have shown that bipolar disorder involves microglial activation and alterations in peripheral cytokines and have pointed to the efficacy of adjunctive anti-inflammatory therapies in bipolar depression.”

They summarize their findings by stating:

“The presence of active microglia and increased proinflammatory cytokines in bipolar disorder suggests an important role of inflammatory components in the pathophysiology of the disease, as well as a possible link between neuroinflammation and peripheral toxicity.”

 

Biological PsychiatryInflammatory microglial activation due to a dysregulated immune system is identified as a key factor in psychosis of all types in a paper just published in Biological Psychiatry:

“Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions.”

Microglia are the immune cells of the brain, functioning as macrophages do in peripheral tissues…

“Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model.”

The ‘two-hit’ model features strongly in a multitude of immune and other disorders:

“Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.”

 

Journal of Affective DisordersA study also published recently in the Journal of Affective Disorders highlights C-reactive protein (CRP) as an inflammatory marker in bipolar disorder. The authors note:

“Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder.”

They measured CRP in 107 subjects with bipolar disorder correlated with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as a metric for cognitive function and found a significant association:

“There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile and the 75th percentile of the control group. There was an inverse relationship between CRP levels and performance on RBANS total ; RBANS immediate memory; RBANS attention; RBANS language…”

The authors conclude:

Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.”

 

NeuropsychobiologyCRP also sorts out as a marker of brain inflammation in a study recently published in the journal Neuropsychobiology:

C-reactive protein (CRP), a marker of underlying low-grade inflammation, has been associated with the pathophysiology of bipolar disorder. Additionally, bipolar disorder may be accompanied by functional or structural cerebral alterations. We attempted to discover whether serum high-sensitivity CRP (hs-CRP) levels are linked to the structural volume change of a specific brain region along with cognitive performance.”

Examining the correlation between orbitofrontal cortex volume, CRP and cognitive function in bipolar disorder the authors conclude:

Elevation of serum hs-CRP levels, an indicator of inflammation, may be associated with reduced volume of the orbitofrontal cortex. Persistent inflammation in the euthymic phase of bipolar disorder may involve the pathogenesis or pathophysiology of alteration of the frontal pathway.”

 

Journal of Psychiatric ResearchCytokines, ‘immune messenger molecules of inflammation’, are naturally also observed in bipolar disorder as documented in a meta-analysis recently published in the Journal of Psychiatric Research:

“Bipolar disorder may be associated with peripheral immune system dysfunction…Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states.”

The authors conducted a meta-analysis of eighteen studies with a total of 761 bipolar disorder patients and 919 healthy controls comparing cytokine concentrations and found…

“Overall, concentrations of soluble Interleukin (IL)-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), soluble tumor necrosis factor receptor type 1 (sTNFR1) and IL-4 were significantly higher in bipolar patients compared with healthy controls.”

 

Trends in ImmunologyOf course, pro-inflammatory cytokines have been recognized in the pathophysiology of depression for years as described in a much earlier paper published in the journal Trends in Immunology:

“Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules. In addition, therapeutic administration of the cytokine interferon-α leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been found to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior.”

Regarding the role of stress and the autonomic nervous system in inflammation:

Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways.”

The two-hit model comes into play in the sense that earlier adaptations may set the stage for a subsequent trigger:

“…depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation.”

The authors conclude:

“These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.”

 

Medical HypothesesThe authors of a paper published in Medical Hypotheses describe pro-inflammatory cytokines as a mechanism shared by both bipolar disorder and migraine:

“A bi-directional association between mood disorders and migraine has been consistently reported… we review evidence for the role of inflammatory cytokines in the neurobiology of bipolar disorder and migraine. In addition, inflammation is hypothesized to be a shared pathophysiological mechanism subserving the bipolar disorder and migraine concomitance.”

And it stands to reason that…

“A derivative of this hypothesis is that pharmacological treatments primarily targeting the inflammatory system may have symptom suppressing effects in bipolar disorder.”

 

Journal of Affective DisordersAnother study published in the Journal of Affective Disorders examines the specific inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in regard to bipolar disorder and response to lithium:

“The role of inflammation in bipolar disorder has recently emerged as a potential pathophysiological mechanism. Tumor necrosis factor-alpha (TNF-α) modulation may represent a pathogenic molecular target and a biomarker for staging bipolar disorder. In this context, the possible association between lithium response and TNF-α level was examined.”

The authors assessed the TNF-α level in 60 bipolar patients receiving lithium therapy in correlation with the ALDA lithium response scale (LRS) to evaluate longitudinal lithium response and found a clear association:

“There was a significant increase in TNF-α level in patients with poor lithium response compared to those with good response, also after controlling for a range of potential confounders.”

Their conclusion is significant both for the role of inflammation marked by TNF-α in bipolar disorder and case management utilizing lithium:

“This study strengthens the hypothesis that TNF-α level may mark or mediate lithium response, and that continuous immune imbalance in poor lithium responders may occasion treatment resistance. Further investigation of immune alterations in treatment-resistant bipolar patients may be productive.”

 

BMC MedicineThe key clinical questions are (1) what are the underlying causes of inflammation? and (2) what sound therapies can be applied to those causes? A paper published recently in BMC Medicine discusses several common contributing causes:

“We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’

The authors discuss several well-known factors including psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. And neuroinflammation is shared characteristic of bipolar disorder, depression, schizophrenia, PTSD, and other psychiatric illnesses:

“There is also evidence that many other major psychiatric disorders are accompanied by activation of inflammatory and cell-mediated immune pathways, for example, mania, schizophrenia, post-traumatic stress disorder (PTSD)…A recent meta-analysis confirmed that mania and bipolar disorder are accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. Based on the first results obtained in schizophrenia, Smith and Maes in 1995 launched the monocyte-T lymphocyte theory of schizophrenia, which considered that activation of immuno-inflammatory processes may explain the neurodevelopmental pathology related to gestational infections. Results of recent meta-analyses showed that schizophrenia is accompanied by activation of inflammatory and cell mediated pathways. PTSD patients also show higher levels of pro-inflammatory cytokines, including IL-1, IL-6 and TNFα…It is evident that the sources of inflammation and immune activation, which play a role in depression, may contribute to the inflammatory burden in patients with mania. Schizophrenia is also associated with some but not all sources of inflammation and immune activation that play a role in depression. For example, a recent review showed that stress and trauma (first and second hits), nutritional factors and vitamin D may play a role in schizophrenia. The strong associations among schizophrenia and smoking, obesity, some atopic disorders, sleep disorders and poor periodontal and oral health may further contribute to the inflammatory burden in schizophrenia patients.”

Regarding the treatment and prevention of bipolar disorder, depression and other psychiatric illnesses the authors conclude:

“The pivotal element is that most of these are plastic, and amenable to intervention, both therapeutic and preventative…Psychiatry largely lacks an integrated model for conceptualizing modifiable risk factors for depression. It has, therefore, lacked conceptually and pragmatically coherent primary prevention strategies, prioritizing the treatment of established disorders. Yet the rationale, targets and imperative to focus on prevention of depression at a population level is clear.”

 

American Journal of PsychiatryFurther evidence for maternal infection as a trigger for autoimmune brain inflammation in bipolar disorder is presented in a study hot off the digital presses from the American Journal of Psychiatry:

“The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features.”

Their data disclosed a specific connection with bipolar disorder with psychotic features:

“…maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features…The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.”

NEJM Journal WatchInterestingly, in a comment on this study published online in NEJM (New England Journal of Medicine) Journal Watch, psychiatrist Joel Yager, MD states:

“Together with research linking maternal influenza to schizophrenia risk, the current finding that influenza during pregnancy greatly increases the risk for bipolar disorder with psychotic features points to potentially similar prenatal mechanisms in the pathogenesis of diverse psychotic disorders. Other research suggests that prenatal priming of such vulnerabilities is in part due to prenatal immune activation of dopaminergic hyperactivity. Overall, such observations hint at common features and mechanisms in psychosis and may lead to better diagnostic conceptualizations.”

 

Progress in Neuro-Psychopharmacology and Biological PsychiatryIt stands to reason then that anti-inflammatory strategies must figure prominently in case management of bipolar disorder and other psychiatric conditions. The authors of a paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry highlight the use of anti-inflammatory agents:

“Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy…During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders.”

Furthermore, the depredations of brain inflammation encompass a wide range:

“Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces ‘sickness behavior’ resembling depressive symptomatology…Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes.”

They identify several anti-inflammatory agents under investigation:

“Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy…”

 

Bipolar DisordersFoods, especially gluten and casein, must never be overlooked as potential triggers of neuroinflammation in bipolar disorder. A study recently published in the journal Bipolar Disorders focuses on this clinically important topic. The authors are also attentive to the issue of gastrointestinal inflammation and compromised barrier function as a sensitizing factor:

Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.”

They examined GI inflammation using ASCA in 207 non‐psychiatric controls, 226 in patients with bipolar disorder without a recent onset of psychosis, and 38 patients with bipolar disorder with a recent onset of psychosis, comparing it to antibodies against gluten, casein, Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV‐1), influenza A, influenza B, measles, and Toxoplasma gondii and found a marked association with gluten and casein:

Elevated ASCA conferred a 3.5–4.4‐fold increased odds ratio of disease association that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups, and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group.”

The authors conclude:

Elevated seropositivity of a GI‐related marker and its association with antibodies to food‐derived proteins and self‐reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder.”

 

Case management of neuroinflammation and the numerous and complex elements of autoimmunity could hardly be covered in a massive textbook much less a post here. A few among many potential therapeutic agents can be considered here by way of example.

Neurochemisty InternationalThe authors of a paper just published in the journal Neurochemistry International offering interesting evidence that alpha-lipoic acid can protect against neuroinflammation in neuropsychiatric disorders:

“Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial…Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity.”

Moreover…

Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson’s, and autism spectrum.”

Of great clinical interest as a benign physiologic intervention…

Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction.”

They treated glial cultures viral mimetic dsRNA LA reduction of the effects of glial signaling, in other words a dampening of inflammation signaling:

LA blunted the dsRNA-stimulated expression of IFNα/β-inducible genes Mx1, PKR, and TLR3. And in polyI:C treated cells, LA promoted gene expression of rate-limiting steps that benefit healthy neural redox status in glutamateric systems. To this end, LA decreased dsRNA-induced inflammatory signaling by downregulating IL-1β, IL-6, TNFα, iNOS, and CAT2 transcripts.”

Considering the crucial role of glutathione metabolism and glutamate expression in regulation of neuroimmunity, their findings in this regard are of particular interest:

“In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cystine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA.

Clinicians should consider the authors’ conclusion:

“This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders.”

 

Medical HypothesesCucurmin, of course, is always worthy of consideration in case management of inflammatory and autoimmune disorders. The authors of a paper published last spring in Medical Hypotheses comment on the use of curcumin for bipolar disorder:

“Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa)…Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.”

 

BMC MedicineInterestingly, aspirin is a potential therapeutic agent for bipolar disorder and other mental illnesses. An excellent paper recently published in BMC Medicine extensively reviews the mechanisms for its beneficial effects. Regarding the position of aspirin and other anti-inflammatory agents in the evolution of therapy for neuropsychiatric disorders:

“Historically, treatment options for common neuropsychiatric disorders, including depression, schizophrenia, and bipolar disorder, have focused on medications that modify the activity of monoamine neurotransmitter systems. Monoamines may play a large role in the pathophysiology of these disorders, but the monoaminergic theory of illness has failed to deliver novel agents beyond the limited treatment options currently available. There is now a clear body of recent evidence to support an etiologic role for other factors in the pathophysiology of depression, schizophrenia, and bipolar disorder, including oxidative and nitrosative stress (O&NS), mitochondrial dysfunction, and activation of the immune-inflammatory system.”

Specifically for aspirin:

“There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer’s disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory ‘braking signals’, including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)-6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.”

Regarding the autoimmune aspect:

“To further support a role for therapeutic agents targeting inflammation in psychiatry, there is a large body of evidence linking autoimmune disease to psychiatric disorders. For example, clinical depression is associated with diverse autoimmune disorders, including diabetes type 1 and 2, inflammatory bowel disease, psoriasis, rheumatoid arthritis, atherosclerosis, lupus erythematosus, and multiple sclerosis (MS). Patients with clinical depression have a high degree of auto-immunity directed against a number of different selfepitopes, including serotonin and phospholipids (for example, cardiolipin and antinuclear factor). Recently, a new type of autoimmune response has been described, which is an autoimmune response secondary to O&NS damage [oxidative and nitrosative damage]. Thus, it is possible that increased O&NS levels may damage endogenous molecules, such as fatty acids and proteins, thereby changing their structure. As a consequence, the O&NS-modified self determinants may be rendered immunogenic, and an autoimmune response is then directed against the modified epitopes (neo-epitopes). For example, clinical depression is accompanied by IgG-mediated immune responses directed against oxidized low-density lipoprotein. Moreover, there is an association between this kind of autoimmune response and progression (or staging) of depression. Consequently, some of these autoimmune responses are significantly higher in depressed individuals with chronic depression (duration of >2 years) compared with patients who are depressed but do not have chronic depression. These findings suggest that O&NS damage, the consequent formation of neo-epitopes, an enhancement of the natural autoimmune response, and even a transition to pathological damaging auto-immunity increase the risk of neuroprogression and of chronic depression.”

The authors also note the interplay between genetic potential and the expression of autoimmunity in bipolar disorder:

“Evidence from the literature on bipolar disorder also supports the role of a genetic component; patients with bipolar disorder and their relatives have been shown to be more prone to develop thyroid auto-immunity, and this association is not attributable to the use of lithium or to the severity of psychiatric symptoms. Moreover, in addition to a higher prevalence of thyroid autoantibodies, patients with bipolar disorder have a higher prevalence of organ-specific autoantibodies, including autoantibodies to hydrogen/potassium ATP and glutamic acid decarboxylase-65. The aforementioned Danish national study confirmed these findings by showing an association of bipolar disorder with a family history of pernicious anemia, and with presence of Guillain-Barré syndrome, inflammatory bowel disease, and autoimmune hepatitis in individual patients.”

As for indicating the use of aspirin:

“Collectively, these findings imply shared immune pathogenic factors for mood disorders, schizophrenia, and organ-specific autoimmune diseases. One of these shared factors is thought to be an intrinsically high activation set-point for the MPS [mononuclear phagocyte system, in this case monocytes present as microglia in the brain]. It is thought that the high activation set-point of these cells of the MPS can be down-regulated by aspirin.”

 

Bipolar DisordersWhile on the topic of aspirin, it’s worth noting a study published last summer in Bipolar Disorders offering evidence that aspirin improves lithium-related sexual in men with bipolar disorder:

“The aim of the present study was to assess the effect of aspirin on lithium‐related sexual dysfunction in men with stable bipolar affective disorder (BAD).”

The authors staged a randomized, double‐blind, placebo‐controlled study, in which 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. They used the International Index for Erectile Function (IIEF) was used to assess sexual symptoms at the start, week 3, and week 6. The results were gratifying:

“Significant effects of time × treatment interaction were observed for total score [Greenhouse–Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse–Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups.”

The authors conclude:

Aspirin effectively improves lithium‐related sexual dysfunction in men with stable BAD.”

Bottom line: There is a massive amount of evidence supporting the importance of assessing and treating neuroinflammation in bipolar disorder and other neuropsychiatric illnesses. This makes necessarily the comprehensive examination of autoimmunity and its numerous underlying contributory causes. Past and future posts focus on this crucial dimension of clinical practice.

Magnesium: insulin, brain, heart and inflammation

PLOS ONEMagnesium may be the critical nutrient most commonly drained by modern environmental stress to suboptimal levels. It seems to be commonly overlooked in clinical practice, even for muscle cramps and spasms for which it is often effective (if given at an adequate dose), and is a prime parasympathetic nervous system support. Recent studies add evidence to its indication for insulin resistance, diabetes, cognitive impairment, atrial fibrillation, cardiovascular disease, and neurogenic inflammation. A recent study published in PLOS One (Public Library of Science) confirms an association of lower levels of magnesium with diabetes and diabetic complications:

“The effect of magnesium (Mg) deficiency on the prevalence of diabetes and diabetic complications has received a great attention. The present study investigated the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications.”

The authors examined data for patients with type 1 diabetes (T1D), type 2 diabetes (T2D), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), along with the incidence of nephropathy, retinopathy or peripheral neuropathy in associateion with serum and urinary magnesium (Mg) levels…

Serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control.”

Importantly, they revealed evidence that statins can contribute to magnesium deficiency:

“There was an early study that showed a reduction trend of serum Mg in the T2D patients treated with 4-month simvastatin treatment compared to T2D patients treated with placebo. In the present study, we found no reduction of serum Mg, but significant reduction of urinary Mg in the T2D patients treated with simvastatin…The above findings suggest that there was a risk for reducing either serum Mg or urinary Mg. Since we have appreciated, based on the above discussion, that Mg appears to play a vital function in the prevention of insulin resistance, diabetes and diabetic complications; In addition, Mg has been also reported to have anti-inflammatory and statin-like effect as well as the stimulating effect of Mg at physiological level on the statin passive diffusion into hepatocytes and their pharmacological actions on cholesterol biosynthesis. Therefore, combination of statin administration with supplementation of certain amount of Mg may be required to avoid the reduction of the Mg level either in the blood or urine caused by supplementation with statin alone. In fact, the combination of Mg with a statin has been recently suggested as a potential and seemingly-promising avenue to reduce cholesterol, C-reactive protein, and cardiovascular disorders.”

The authors sonclude:

“By directly measuring serum and urinary Mg here we demonstrated the significantly low serum Mg level not only in T2D, but also in IFG, IGT, and T1D…In the present study, we demonstrated for the first time that T1D patients also exhibited a significant low of serum Mg level compared to control…We also demonstrated the increase secretion of Mg in urine for both T1D and T2D patients…Therefore, the potential impact of Mg in metabolic syndrome, diabetes and diabetes-related or no-related cardiovascular disorders needs to be received special attention.”

 

NutrientsThese findings were echoed in another study recently published in the journal Nutrients showing that dietary magnesium improves insulin resistance in subjects with metabolic syndrome, and the need for adequate magnesium may not be met through diet. The authors state:

“Many cross-sectional studies show an inverse association between dietary magnesium and insulin resistance, but few longitudinal studies examine the ability to meet the Recommended Dietary Allowance (RDA) for magnesium intake through food and its effect on insulin resistance among participants with metabolic syndrome (MetS). The dietary intervention study examined this question in 234 individuals with MetS.”

They assessed magnesium intake, along with fasting glucose, insulin and insulin resistance estimated by the standard homeostasis model assessment (HOMA-IR) for 234 individuals with MetS at baseline, 6, and 12 months. Clinicians really need to bear in mind what their data reveals:

“Baseline magnesium intake was 287 ± 93 mg/day, and HOMA-IR, fasting glucose and fasting insulin were 3.7 ± 3.5, 99 ± 13 mg/dL, and 15 ± 13 μU/mL, respectively. At baseline, 6-, and 12-months, 23.5%, 30.4%, and 27.7% met the RDA for magnesium. After multivariate adjustment, magnesium intake was inversely associated with metabolic biomarkers of insulin resistance. Further, the likelihood of elevated HOMA-IR (>3.6) over time was 71% lower in participants in the highest quartile of magnesium intake than those in the lowest quartile. For individuals meeting the RDA for magnesium, the multivariate-adjusted OR for high HOMA-IR over time was 0.37.”

In other words, magnesium from diet alone just doesn’t cut it for most people in regard to insulin resistance. The authors conclude:

“These findings indicate that dietary magnesium intake is inadequate among non-diabetic individuals with MetS and suggest that increasing dietary magnesium to meet the RDA has a protective effect on insulin resistance…Since this population has a higher risk of cardiovascular disease and type 2 diabetes, dietary behaviors that have the ability to impact insulin resistance can have far-reaching clinical implications.”

 

The Journal of Neuroscience 33(19)Of premiere importance is the role that magnesium plays in neuroplasticity and protects against loss of cognitive function. A study published recently in The Journal of Neuroscience provides evidence for the benefit of magnesium in Alzheimer’s disease:

“Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits…”

They examined the effect of magnesium levels on AD-like pathologies in the brains of their study subjects (a a transgenic (Tg) mouse model of Alzheimer’s disease), including Aβ (amyloid beta) plaque formation, molecules necessary for neuronal energy metabolism, and influence on signaling pathways involved in synaptic plasticity and density. Their data showed a remarkable correlation:

MgT treatment reduced Aβ plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression… In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and β-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPβ and β-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices.”

Reduction of amyloid plaque by magnesiumIn other words, the magnesium treatment profoundly ameliorated neuronal damage and memory loss. The authors note some fascinating observations:

“Our studies demonstrate that an increase in magnesium intake enhances memory in young rats, reverses memory decline in aged rats (Slutsky et al., 2010), and prevents memory deterioration a mouse model of AD (the present study). However, it is intriguing that after long-term magnesium supplementation, the Mg2+ concentration in the CSF only increased by 15% (Slutsky et al., 2010) and the total magnesium in brain increased by 30%. Can small increases in [Mg2+]CSF have major impact on synapse density? In a separate study, we found that increasing extracellular Mg2+ by 15% led to an ∼50% increase in synapse density in cultured hippocampal synapses (unpublished observations). These data suggest that hippocampal synapse density might be very sensitive to small changes in extracellular Mg2+ concentrations. Under normal physiological conditions, whole-body magnesium is tightly regulated by kidney function. Daily fluctuation of plasma magnesium associated with food intake is <0.1 mm above a baseline of 0.7 mm (Witkowski et al., 2011). Brain magnesium is supposed to be more stable because the blood–brain barrier isolates the brain from daily fluctuations in blood magnesium. Therefore, despite the high sensitivity of the synapses to Mg2+ concentration, synapse density is likely to be stable under physiological conditions. Conversely, if brain magnesium is reduced under pathological conditions, this might have a profound impact on synapse density and memory function. Interestingly, in the hippocampus of AD patients, the total magnesium level is reduced by 18% (Andrási et al., 2005).”

They conclude:

“Therefore, restoration/elevation of brain magnesium in AD patients might be beneficial for ameliorating the cognitive deficits of AD. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.”

 

The Journal of NutritionOf course there is an abundance of evidence for the importance of magnesium in cardiovascular disease. A paper just published in The Journal of Nutrition links magnesium intake with death from all causes in people at high cardiovascular risk. The authors state:

“The relation between dietary magnesium intake and cardiovascular disease (CVD) or mortality was evaluated in several prospective studies, but few of them have assessed the risk of all-cause mortality, which has never been evaluated in Mediterranean adults at high cardiovascular risk. The aim of this study was to assess the association between magnesium intake and CVD and mortality risk in a Mediterranean population at high cardiovascular risk with high average magnesium intake.”

They examined data for 7216 men and women assigned to one of two Mediterranean diets (supplemented with nuts or olive oil) or advice on a low-fat control diet and, in particular, assessed the associations between yearly repeated measurements of magnesium intake and mortality…

“After a median follow-up of 4.8 y, 323 total deaths, 81 cardiovascular deaths, 130 cancer deaths, and 277 cardiovascular events occurred. Energy-adjusted baseline magnesium intake was inversely associated with cardiovascular, cancer, and all-cause mortality. Compared with lower consumers, individuals in the highest tertile of magnesium intake had a 34% reduction in mortality risk. Dietary magnesium intake was inversely associated with mortality risk in Mediterranean individuals at high risk of CVD.”

 

PACEAs expected when considering the critical role of magnesium in neuromuscular excitability, magnesium should be considered in case management of cardiac arrhythmias. The authors of a paper published on magnesium and atrial fibrillation in the journal PACE (Pacing And Electrical Physiology) state:

“Magnesium (Mg) is an important intracellular ion with cardiac metabolism and electrophysiologic properties. A large percentage of patients with arrhythmias have an intracellular Mg deficiency, which is out of line with serum Mg concentrations, and this may explain the rationale for Mg’s benefits as an atrial antiarrhythmic agent.”

They further note:

“A current limitation of antiarrhythmic therapy is that the potential for cardiac risk offsets some of the benefits of therapy. Mg enhances the balance of benefits to harms by enhancing atrial antiarrhythmic efficacy and reducing antiarrhythmic proarrhythmia potential as well as providing direct antiarrhythmic efficacy when used as monotherapy in patients undergoing cardiothoracic surgery.”

 

American Journal of Clinical NutritionIschemic heart disease (IHD) is also influenced by magnesium sufficiency as documented in a study published in the American Journal of Clinical Nutrition. The authors set out to…

“…investigate whether urinary magnesium excretion and plasma magnesium are associated with IHD risk.”

To do so they examined 7664 subjects without for urinary magnesium excretion as measured in 2 baseline 24-h urine collections and found that…

“Mean ± SD urinary magnesium excretion was 4.24 ± 1.65 mmol/24 h for men and 3.54 ± 1.40 mmol/24 h for women. During a median follow-up of 10.5 y, 462 fatal and nonfatal IHD events occurred. After multivariable adjustment, urinary magnesium excretion had a nonlinear relation with IHD risk. The lowest sex-specific quintile (men: <2.93 mmol/24 h; women: <2.45 mmol/24 h) had an increased risk of fatal and nonfatal IHD (multivariable HR: 1.60) compared with the upper 4 quintiles of urinary magnesium excretion. A similar increase in risk of the lowest quintile was observed for mortality related to IHD (HR: 1.70). No associations were observed between circulating magnesium and risk of IHD.”

This interesting study demonstrates two clinically significant points: (1) magnesium status is indeed associated with the risk of ischemic heart disease, and (2) serum magnesium is a very poor indicator of magnesium status (a fact that all experienced clinicians should be aware of). The authors conclude:

Low urinary magnesium excretion was independently associated with a higher risk of IHD incidence. An increased dietary intake of magnesium, particularly in those with the lowest urinary magnesium, could reduce the risk of IHD.”

 

Heart Failure ReviewsPerhaps of premiere importance is the fact that suboptimal magnesium promotes neurogenic inflammation that can contribute to not only cardiovascular disease but any inflammatory disease, and be a contributing factor in the progression of intestinal permeability. This is presented in a paper published in Heart Failure Reviews:

“Magnesium is a micronutrient essential for the normal functioning of the cardiovascular system, and Mg deficiency (MgD) is frequently associated in the clinical setting with chronic pathologies such as CHF, diabetes, hypertension, and other pathologies. Animal models of MgD have demonstrated a systemic pro-inflammatory/pro-oxidant state, involving multiple tissues/organs including neuronal, hematopoietic, cardiovascular, and gastrointestinal systems; during later stages of MgD, a cardiomyopathy develops which may result from a cascade of inflammatory events. In rodent models of dietary MgD, a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide among others, was observed within days (1–7) of initiating the Mg-restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early “neurogenic inflammation” phase may be mediated in part, by the Mg-gated N-methyl-D-aspartate (NMDA) receptor/channel complex.”

Of the greatest importance for clinical case management…

“Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory-motor C-fibers to promote the subsequent pro-inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE2 levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants.”

Recall that sensory-motor C-fibers are also involved in chronic pain. And of great interest to practitioners managing autoimmunity and gastrointestinal infection:

“Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1–3 weeks MgD) inflammatory/pro-oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co-existing with other pathologies, may enhance the risk of developing chronic heart failure.”

 

Clinical note: Suboptimal magnesium levels are so common, and involved in so many pathophysiological processes (only a fraction of which have been described here)—that so often go unrecognized in clinical practice—I urge practitioners to keep this in mind.