Are Chronic Inflammation and its Metabolic Counterpart, Insulin Resistance, the Common Denominators for All Chronic Behavioral and Neurodegenerative Disorders? – A Review Of the Evidence – Part II

In part I of this series I reviewed the paper “Immune aging, dysmetabolism, and inflammation in neurological diseases” by Deleidi et al (1) in which it was stated that the key cell in the CNS that appears to be most responsible for much of the damage seen in the CNS as the result of chronic inflammation is the main innate immune cell of the brain, microglia.  As noted by the authors, chronic inflammation can upregulate activity of microglia leading to increased CNS inflammation and a whole host of mood, behavioral, and neurodegenerative disorders.  In part II of this series I would like to discuss microglia in more detail by reviewing the paper “The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders” by Reus et al (2).

INFLAMMATION AND PSYCHIATRIC DISORDERS

Reus et al (2) begin their paper with a review of the relationship discussed in part I of this series between inflammation and mood and behavioral disorders:

“A growing body of evidence suggests that many psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, and autism are associated with distinct inflammatory mechanisms in the periphery and in the central nervous system.”

What is the source of this inflammation?  The quote below suggests it is the typical inflammatory disorders presented by our patients every day:

“Risk factors for MDD and BD include medical conditions associated with chronic

inflammatory and immunological alterations, such as rheumatoid arthritis, obesity and diabetes.”

The authors then go on to point out that neurologic inflammation is typically associated with what was mentioned in part I of this series, microglial activation:

“Inflammation in the context of the nervous system, termed ‘neuroinflammation’, has been reported in patients with psychiatric disorders and is typically associated with microglial activation.”

MICROGLIAL ACTIVATION AND ITS ROLE IN PSYCHIATRIC DISORDERS

The next quote discusses some basic facts about microglia:

“Microglia are CNS-resident cells that are usually the first to be activated in response to tissue damage or brain infections.  These small cells have several functions described, including (but not limited to): pathogen recognition, phagocytosis, antigen presentation, and synapse remodeling.  Non-activated microglia termed ‘quiescent’ or ‘resting’ microglia are constantly surveilling the surrounding environment in non-pathological conditions.  In response to changes in the environment, microglial cells can be activated by changing their morphology and function.”

As I hope you can see, in many ways microglia act just the same as most other immune cells in the body.  What happens when microglia are activated?  This was discussed briefly in part I.  The next quote provides much more detail:

“Microglial activation can be divided into two distinct types: a classical M1 and an alternative M2 activation.  In the M1 activation, microglial cells may become hyperramified or ameboid/phagocytic, and may synthesize proinflammatory molecules (interleukin 1β – (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, among others), superoxide radicals, glutamate, nitric oxide (NO) and ultimately clear infections and repair tissues.”

Thus, M1 activation represents a process that is typical for the immune system outside of the CNS in that it, when activated, generates inflammatory and other compounds designed to cope with environmental stressors, especially infections.  M2 activation of microglia demonstrates properties typical of the aspects of the immune system that are designed to reduce inflammatory activity and tissue damage plus stimulate repair:

“Alternatively, M2 activation, which can be triggered by cytokines such as IL-4, IL-13, or IL-25, has been associated with a release of anti-inflammatory cytokines such as IL-10, insulin-growth factor-1 (IGF-1), transforming growth factor-β (TGF-β), and neurotropic factors, which facilitate healing and limit neuronal injury.  The nature and magnitude of the injury, along with several other factors, can influence the development of these distinct microglial phenotypes.”

Next, Reus et al (2) make the very important point that, because microglial activation can take two very different forms, it is not enough just to know that microglia have been activated.  We must also know the type of activation:

“Most importantly, identifying activated microglia in a pathological condition, although being a marker of inflammation, does not allow for an understanding of the inflammatory process.  Thus, only by determining the phenotype of microglia can one identify its role in cytotoxicity and/or neuroprotection.”

Please note again that, contrary to what has generally been stated about microglia in the past, not all activated microglia act in a proinflammatory, destructive manner.  Some are actually vital for tissue building and repair.

Next, the authors again point out the important relationship between alteration of microglia and psychiatric disorders:

“Several studies in the past year speculated that alterations in the number and/or morphology of microglial cells are involved in cognitive and behavioral changes observed in psychiatry disorders.”

However, the authors also emphasize what often is not considered in relationship to microglia and psychiatric disorders – that microglia activation can take on two very different forms:

“…given that microglia can be activated in either a cytotoxic or a neuroprotective way, characteristics of the microglial activation assessed in a specific condition need to be taken into account.  This review article aims to summarize evidence of inflammation and in major psychiatric disorders, such as major depression, bipolar disorder, schizophrenia, and autism, including the role it plays in their progression and therapeutics.”

MICROGLIAL ACTIVATION AND MAJOR DEPRESSIVE DISORDER (MDD)

This section begins with some basic information on MDD:

“MDD is considered a critical public health problem, and it is estimated that approximately 350 million individuals are affected worldwide.  In addition, almost 1 million lives are lost yearly due to suicide, which translates to 3000 suicide deaths every day.”

Of course, in the past it was generally accepted, as we all know, that depression is mainly an issue of aberrant neurotransmitter activity:

“Until recently, the monoaminergic hypothesis appeared to be the most widely accepted theory for depression.”

However, as I have been discussing, more recent research suggests that neurotransmitters do not tell the whole depression story:

“…a series of new studies have shown that other pathways involved with neuroplasticity or intracellular signaling cascades would be directly or indirectly responsible for the mood dysregulation, as well as to the mechanism of action of antidepressant drugs.”

The next paragraph goes into detail about the relationship between inflammation and depression, ending with an intriguing statement that suggests that antidepressant drugs may be effective due to anti-inflammatory activity:

“Since patients with autoimmune and inflammatory disorders, such as diabetes and fibromyalgia, present with depressive symptoms, it has been proposed that depression may be linked to inflammation.  In fact, patients with depression have been shown to present an increase in serum levels of proinflammatory cytokines, such as IL-1, IL-6, IL-8, IL-12, interferon-gamma (IFN-gamma) and TNF-α.  In addition, elevated plasma levels of IL-1β, IL-1 receptor antagonist, IL-5, IL-6, IL-7, IL-8, IL-10, granulocyte colony-stimulating factor (G-CSF), and IFN-gamma have been reported in patients during ongoing depression.  Of note, cytokines were reduced to normal levels after 12 weeks of treatment with antidepressants.”

Is the clinical effect of antidepressants actually due to anti-inflammatory properties?

As we all know, antidepressants such as fluoxetine (Prozac and others) often deliver inconsistent results with depression.  However, when they do show efficacy, could the reason be reduction of inflammation as opposed to the generally accepted mechanism of serotonin optimization?  This question has recently been explored in other papers which I will review in detail in the next installment.  However, Reus et al (2) have some compelling comments on this controversy.  First consider the following:

“…acupuncture and fluoxetine treatments reduced IL-1β levels in responders, whereas acupuncture was also able to restore the balance between Th1 and Th2 systems by attenuating TNF-α concentration and INF-gamma/IL-4 ratio toward the control level.”

In addition, antidepressant drugs appear to have an impact on microglial regulation:

“Antidepressant drugs used to treat depression also act in microglial regulation.  In fact, selective serotonin reuptake inhibitors (SSRIs) potently inhibit microglial TNF-α and nitric oxide production induced by lipopolysaccharide (LPS)…”

Furthermore:

“Fluoxetine, an SSRI, also reduced the microglial activation in dopaminergic neurons induced by an animal model of Parkinson, and also prevented LPS-induced degeneration of nigral dopaminergic neurons by inhibiting microglia-mediated oxidative stress.”

Lipopolysaccharides (LPS) are endotoxins (metabolic waste products) produced primarily by gut microflora that can be highly proinflammatory when absorbed in scenarios such as leaky gut.

With the above data in mind, Reus et al (2) conclude:

“…the antidepressant effects of classic and new modulators could be mediated, at least in part, by its effects on regulating the immune system.”

Unfortunately, the studies on the subject of the relationship between antidepressants and neurologic inflammation all make it clear that, just because antidepressants reduce inflammation does not mean that this is the reason they are clinically effective with some cases of depression.  In other words, it could be just an association and not a true cause and effect phenomenon.

As I mentioned, I will explore this controversy in more detail in the next installment of this series.

STILL MORE INFORMATION ON THE IMPACT OF MICROGLIAL ACTIVATION

The next few quotes point out that, similar to cortisol, microglia will activate in scenarios that are considered stressful:

“These findings support the theory that microglia plays a pivotal role in modulating the impact of stress.”

Furthermore:

“…morphological activation of residential microglia was induced by exposures to acute stress.”

Finally:

“…studies which showed microglial activation in response to stress could be related to an acute response to stress.  In addition, these changes could be related not only to the development of depression, but also anxiety.”

However, are microglia activated only by psychological stress, i.e. worry?  No.  For, microglia can also be activated from input from the peripheral nervous system:

 “Microglia exerts an inflammatory role against danger signals from both the central and peripheral nervous system.”

Is there a link between microglial activation and suicide?

Reus et al (2) state:

“Microglial activation was also greater in the ventral prefrontal white matter in individuals who committed suicide.”

In addition:

“…Steiner et al. did not find any evidence of microglial activation in the same brain areas from patients who were suffering from depression, but did find in patients who had committed suicide, suggesting that microglial activation might be a consequence of presuicidal stress.”

Can sleep deprivation affect microglial activation?

Reus et al (2) point out the following concerning microglial activation and sleep:

“Maternal sleep deprivation, an animal model of depression, inhibited neurogenesis through inflammatory cytokines (IL-1β, IL-6, and TNF-α) released from activated microglia in young offspring rats; these effects were associated with memory impairment and anhedonic behavior.”

Cortisol and microglial activation

As you might expect, cortisol elevations have an intimate relationship with microglial activation.  However, this relationship appears to be dose dependent:

“…it is possible that cortisol signaling in microglia may play an important role in the inflammatory process related to depression; these effects were dependent on the corticosterone dose, though.  In fact, corticosterone administration in low dose was able to reverse microglial activation induced by stress and adrenalectomy.”

Therefore, as you can see, both low and high amounts of cortisol are related to microglial activation.  Since, in my experience, low cortisol readings seen with salivary cortisol testing are as frequent as high levels, it should be kept in mind that it is highly likely that, when these suboptimal cortisol levels are seen, mood changes related to microglia-induced CNS inflammation are a distinct possibility.

Glutamate and microglial activation

Based on information about monosodium glutamate (MSG) that we have seen in the nutritional literature over the years, it is recognized that glutamate in high levels, whether ingested or produced endogenously, can have a potentially proinflammatory, excitatory, and destructive impact on the CNS.  Are these adverse impacts of glutamate related to microglial activity?  Consider the following statements from Reus et al (2):

“Studies have shown that glutamate, an important neurotransmitter in the CNS that plays a key role in the pathophysiology of depression, is also involved in microglial toxicity.  Inflammatory cytokines are able to decrease the expression of the glutamate transporter and increase glutamate release from astrocytes.  Activation of microglia by inflammatory cytokines, in turn, can induce a release of glutamate that contributes to neuronal damage during neuroinflammation.”

Of course, the negative impact of microglia-induced glutamate release does not stop there:

“Moreover, glutamate accumulation causes an increase of intracellular Ca2+, which in turn may lead to the production of reactive species (ROS) due to mitochondrial dysfunction and reduction of antioxidant capacity.  Thus, mitochondrial dysfunction and oxidative stress contribute to glutamate excitotoxicity and consequently increased proinflammatory genes.  Glutamate and their receptors play an important role in the pathophysiology of depression.  Indeed, patients with depression presented a significant increase in serum glutamate levels when compared with healthy controls.”

As I hope you can see, our longstanding belief that mood disorders such as depression are nothing more than an issue of neurotransmitter imbalance must now be relegated to the dusty corner of history now occupied by the typewriter and the horse and buggy.  All three, while still useful, are woefully limited in their applicability by today’s standards and body of knowledge.  While I am not stating that we now discard all efforts to optimize neurotransmitter status with depressed patients, we must now recognize, as evidenced by the many patients who did not respond as well clinically as we would hope, focusing on neurotransmitters is no longer enough.  To gain predictable positive responses in a cross section of patients we must now treat mood disorders just like we have treated so many somatic issues from a functional medicine standpoint.  These are multifaceted metabolic issues that also require optimization of inflammatory mediators, insulin metabolism, free radical production, mitochondrial function and all the environmental stressors involved in their creation that include but are not limited to poor nutritional intake.

MICROGLIAL ACTIVATION AND BIPOLAR DISORDER

Of course, bipolar disorder (BD) is nothing more than depression interspersed with periods of mania.  Reus et al (2) state:

“BD is a severe mood disorder characterized by recurrent episodes of mania followed by depression.  Although the clinical characteristic for the diagnosis of BD is the presence of manic symptoms, depression represents the predominant mood state in patients with BD type I and BD type II.”

As you might expect, conventional thinking for many years has suggested that BD is simply an issue of aberrant neurotransmitter activity.  The authors point out that, as with depression, this is not the case:

“The pathophysiology of BD has been attributed to deficits in monoamine neurotransmitters, such as dopamine.  However, the neurobiology of BD, as well as the mechanism of action of mood stabilizers used to treat BD, is not fully elucidated.  Thus, it is possible that other pathways besides the monoaminergic system could be involved.  Recently, mood disorders are increasingly being recognized as inflamed moods.  One theory suggests that in the BD the immune system is chronically activated by microglia, which in turn produces cytokines that render the brain to a vulnerable and unstable state, precipitating mood disturbances.”

Evidence of this comes from several studies:

“…higher levels of IL-1β were associated with dysfunction and increased suicide risk in patients with BD.  Changes in sleep pattern were also observed in patients with BD, with an increase of IL-6 in peripheral monocytes.  Furthermore, Barbosa et al demonstrated an increase in proinflammatory cytokine levels in BD.”

Then, of course, there is, as I have discussed repeatedly, the inflammation-induced disturbances in tryptophan metabolism as seen with alteration of kynurenine metabolites.  Reus et al (2) point out:

“In euthymic patients with BD, an increase in blood kynurenine concentrations and in the kynurenine to tryptophan ratio was also observed.  The kynurenine pathway plays an important role in psychiatric diseases; this pathway is an alternate route of tryptophan metabolism that decreases serotonin neurotransmission.”

In the next quote the authors provide a concise overview of the kynurenine pathway that I have discussed before:

“Moreover, stimulated microglia may promote expression of cytokines, such as IFN-gamma, a potent activator of the kynurenine pathway (KP).  IFN-gamma increases the activity of indoleamine 2,3-dioxygenase (IDO), consequently increasing quinolinic acid (QUIN), which causes excitotoxicity mediated by the NMDA receptor.  In the CNS, activated microglia and infiltrating macrophages are considered the main producers of QUIN.”

Could drugs commonly used with BD have anti-inflammatory properties?

As with depression, could the drugs commonly used with BD that were always thought to function purely by optimizing neurotransmitter activity also have an impact on microglial activation and inflammation?  Reus et al (2) comment on two commonly used drugs with BD, valproate and lithium.  First, concerning valproate:

“Valproate (VPA), a histone deacetylase inhibitor (HDACi), seems to play an important role in managing activated microglial cells.  Cells pretreated with VPA showed decreased levels of proinflammatory factors, which were concentration- and time-dependent.  The anti-inflammatory effects of VPA appear to be based on its ability to induce apoptosis in activated microglia.”

Concerning lithium:

“Lithium, a mood stabilizer, was also able to significantly inhibit LPS-induced microglial activation and pro-inflammatory cytokine production in vitro.

With the above in mind, the authors conclude:

“Altogether, these results point to an interesting relationship between the mechanism of action of these classic mood stabilizers (Lithium and VPA) and microglial cells.”

MICROGLIAL ACTIVATION AND SCHIZOPHRENIA

Certainly one of the most challenging mood disorders faced by clinicians over the years is schizophrenia.  Reus et al provide a brief clinical overview:

“Schizophrenia is a chronic and debilitating disorder that affects 0.5-1% of the world population.  Patients with this disorder present positive and negative symptoms.  Positive symptoms are characterized by extra feelings or behaviors, such as hallucinations and delusions.  On the other hand, negative symptoms are associated with lack of behaviors, for example, apathy and loss of interest in everyday activities.”

Of course, as you might expect, conventional thinking suggests that schizophrenia is purely a disorder of neurotransmitter metabolism.  The authors state:

“Evidence suggests that the dopamine dysfunction hypothesis, which involves hyperstimulation of dopaminergic D2 receptors in certain parts of the brain, may lead to positive symptoms.  The glutamatergic hypofunction hypothesis of schizophrenia could be responsible for the negative symptoms.”

Could neuroinflammation also be a causative factor?  Reus et al (2) comment:

“Additionally, neuroinflammation has been linked to schizophrenia, as well.  One theory suggests that maternal immune activation during pregnancy is a risk factor for the progeny to develop schizophrenia in adulthood.”

What would cause the maternal immune activation?  According to the authors, it could be infection:

“…studies showed an association between Toxoplasma gondii and early-onset schizophrenia, and maternal genital/reproductive infections during periconception increased the risk of schizophrenia in offspring.”

Does microglial activation also play a role?  As you might expect, research suggests this:

“Microglial activation and an increase in microglial cells in the brain of schizophrenic patients have been reported in post-mortem studies.  An increase in microglial cells was also demonstrated in schizophrenic patients who had committed suicide.  A positron emission tomography (PET) study showed microglial activation in recent-onset schizophrenics within the first 5 years of disease.”

What cytokines might be involved with microglial activation in schizophrenics?  Reus et al (2) point out:

“Schizophrenia is known to be associated with alterations in the immune system, such as increased cytokine levels.  In a meta-analysis, IL-1β, IL-6, and TGF-β (which also has neuroprotective and anti-inflammatory effects in the CNS) were augmented during an acute relapse in patients and in the first episodes of psychosis.”

Reus et al (2) conclude the section on schizophrenia by theorizing that efforts to reduce inflammation and/or enhance anti-inflammatory activities in the body may be a viable approach:

“In conclusion, inhibition of pro-inflammatory cytokines or enhancement of anti-inflammatory mediators in schizophrenic patients may be a beneficial strategy to prevent the devastating consequences of this illness with respect to neuronal damage and function.”

MICROGLIAL ACTIVATION AND AUTISM

Of all the behavioral and degenerative neurologic diseases that tend to come our way in everyday clinical practice are there any that are more discussed and controversial than autism?  For, it seems like every day we hear new and sometimes conflicting theories as to causation. As will be demonstrated below, could the fact that so many autistic patients present findings consistent with microglial activation bring some much needed simplicity and clarity?  Consider the following:

“Recent studies have demonstrated a relationship between autism and inflammation dysregulation/alteration. Microglial activation has also been reported in patients with autism spectrum disorder (ASD).  For instance, Tetreault et al. reported an increase of microglial cells in cortical areas (fronto-insular (FI) and visual cortex (VC)) from individuals diagnosed with autism.  Moreover, in a postmortem study microglia was found to be augmented in individuals with autism when compared with healthy controls, and a PET revealed that young adults with ASC had increased markers of microglial activation in a wide range of brain areas, including the cerebellum, brainstem, frontal cortex, anterior cingulate cortex, corpus callosum, temporal cortex, and parietal cortex.  Dendritic cells, which are important in modulating immune responses, were found to be increased in the amygdala of individuals with ASD in magnetic resonance imaging (MRI) study.”

What happens when LPS (lipopolysaccharides, also known as endotoxins, that are produced by gut microflora) is introduced into mice?  As you might imagine, this question is highly clinically significant given all the controversy as to whether gut disturbances can play a role in ASD.  The authors point out:

“…LeBelle et al. revealed that pregnant mice exposed to LPS had offspring with increased forebrain microglia and autistic behavior.  In addition, LPS exacerbated glial activation in the hippocampus and the cerebellum, as well as behavioral changes in the gestational period.  Thus, it is possible that prenatal inflammation might be involved, at least in part, to microglial activation in ASD.”

What about glutamate dysfunction?  As was mentioned above, one reason why microglial activation is so disruptive to neurologic function is its adverse impact on glutamate activity.  Reus et al (2) state the following:

“Glutamate dysfunction has been reported also in ASD.  A study showed that autistic patients exhibited higher glutamate concentration…”

In addition, disturbances were found with GABA and the GABA/glutamate ratio.  These findings led the authors to conclude:

“Altogether, these results suggest that an imbalance in GABA and glutamate neurotransmission might be related to neuroinflammation in ASD.  Thus, glutamatergic modulators could be promising to treat ASD spectrum to ultimately reduce glutamatergic excitotoxicity and consequently microglial activation.”

CONCLUDING THOUGHTS FROM REUS ET AL

As compelling as their data is relating many clinically significant neurologic disorders to inflammation and upregulation in microglial activity, Reus et al (2) conclude their paper with some somewhat sobering but important observations.  First and foremost, the vast majority of the findings are observational, pointing out associations without actual proof of cause and effect.  Therefore, it appears that neuroinflammation is only part, albeit a very important part, of the story and it is premature to eliminate clinical interventions used in the past in favor of just focusing on reducing inflammation and optimizing microglial activity.  The authors point out:

“Microglial activation and neuroinflammation are evident in psychiatric conditions and have been reported by preclinical and clinical studies.  However, the pathological mechanisms involved in the microglial dysfunction are still not fully elucidated.  Of note, it remains unclear whether microglia activation can lead to the onset of psychiatric disorders and consequently to a neuroinflammatory process.  More specifically, even though microglial activation can present two opposite phenotypes, the majority of the studies do not take these phenotypes into account when assessing microglial activation in different disorders.  In other words, we can only infer whether a particular disorder is associated with the M1 or M2 phenotype based on the reported inflammatory markers that these patients present.  In addition, many studies show peripheral inflammation in psychiatric disorders; however, increased inflammatory markers in the periphery are not synonyms of microglial activation in the CNS.”

SOME FINAL THOUGHTS

Please keep in mind that it is not my intention that the caveat in the above quote discourages you from aggressively searching for indicators of chronic inflammation in your patients with mood and neurodegenerative disorders and addressing them whenever possible.  For, as I hope I have demonstrated and will continue to demonstrate in this series, the evidence is overwhelming that inflammation plays a key role in neurologic disorders.  Unfortunately, what the research presented in this series cannot optimally address is the role of inflammation in the neurologic disorder in your unique and individual patient.  Therefore, what I am presenting should not discourage you in any way from using other, more conventional approaches that are intended to optimize neurotransmitters.  Rather, it is designed to give you another viable clinical option for those many patients who do not respond well to either pharmaceutical or alternative modalities geared towards neurotransmitter optimization.

In part III of this series I will begin by exploring in more detail the intriguing hypothesis that pharmaceuticals used for mood and behavior disorders, when effective, are effective because of their anti-inflammatory properties rather than their impact on neurotransmitter metabolism.  Also, I will review still more papers that support that idea that mood/behavior and neurodegenerative disorders have a significant inflammatory basis. 

Moss Nutrition Report #267 – 02/01/2016 – PDF Version

REFERENCES

  1. Deleidi M et alImmune aging, dysmetabolism, and inflammation in neurological diseases. Frontiers in Neuroscience. 2015;9.
  2. Reus GZ et alThe role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015;300:141-54.