Neuroinflammation and Excitotoxicity Part 1: Depression

My introduction to this topic was in the form of a suicidal patient, who was pulled out of his despair by a quick IV.  

What was this magical treatment and how did it work?  After witnessing the profound change in affect this medication brought about in only 10 minutes, I was completely intrigued.  The drug used was Ketamine; a dissociative anesthetic used primarily for emergency or battlefield surgery, for pain and most recently for mental health conditions.  The interesting thing about Ketamine from a surgical point of view is that it is one of our only anesthetics that does not significantly depress our breathing reflex, thus making it generally a safer alternative for short procedures and pediatric cases (1).  New research has also found this drug to be neuroprotective, anti-tumor and anti-inflammatory.  How could an anesthetic, with anti-inflammatory properties possibly help a suicidal patient?  Enter inflammation and excitotoxicity…..

Most of us have a general idea as to what inflammation entails. Redness, pain, fatigue and increased activity of the immune system all come to mind,  how about when that inflammation occurs in the brain or central nervous system?  

Neuroinflammation is the general term used to describe that very process. The cells involved in inflammatory signaling are different, but this process can occur within the brain, and like inflammation anywhere else in the body, if it continues chronically; it’s a very bad thing.

Neuroinflammation can be the result of head trauma, viral or bacterial infections, environmental or metabolic toxicity, malignancies, or in response to the inflammatory signals occurring elsewhere in the body.

In the 1950’s the theory of mental illness as simply a neurotransmitter imbalance began to take hold.  The “monoamine theory” was used to describe depression as a state of low serotonin or dopamine, and drugs such as tricyclic antidepressants, MAOI’s and SSRI’s were sold in hopes of forever ridding our society of mental health concerns.  Unfortunately, we soon found out that response rates for antidepressants were disappointing.  Ten years later, researchers studying infection noted that sick people (and research animals),  behaved very similar to depressed people.  They withdrew, they had major fatigue, aches, and pains, they wanted to sleep more, not eat and felt down; leading researchers to coin the term “sickness behavior”.  Sickness behavior is triggered when proinflammatory cell messengers called cytokines produce widespread immune activation in order to fight an infection.  It is an adaptive response to infection, allowing the individual to rest and protecting the community from a potentially contagious disease.  The cytokines involved in this process mediate behavior through triggering inflammation in the brain or by sending cytokines directly to the brain through nerves near the site of inflammation (2).  

The specific cytokines involved in sickness behavior include interleukin (IL) 1 (IL-1α and IL-1β), IL-6, and tumor necrosis factor α (TNF-α) (3).

Interestingly it turns out that not only does sickness behavior mimic depression, but inflammatory biomarkers like IL-6 and TNF-α are found in higher quantities in the blood of people with major depressive disorders.   To further support the relationship between depression and inflammation consider the following:

 • Depression frequently is comorbid with many inflammatory illnesses- people with inflammatory conditions have higher rates of depression (RA, Lupus, Inflammatory bowel disease).

• Exposure to immunomodulating agents may increase the risk of developing depression; such as seen in hepatitis patients receiving interferon (inflammatory agent use to stimulate the immune system to kill hepatitis infected cells).

• Stress can activate proinflammatory pathways - Stress and depression are linked.

• Antidepressants can decrease inflammatory response. 

• Inhibition of inflammatory pathways can improve mood - Supplements like EPA fish oil or Turmeric have shown benefit in depression and act through ameliorating inflammation.

The inflammatory and monoamine theory of depression are not exclusive.  When inflammation is present in the brain, it activates an enzyme called Indoleamine 2,3 dioxygenase (IDO).  This diverts the precursor to serotonin; the amino acid L-tryptophan, away from its normal pathway to one that synthesizes kynurenine and then the neurotoxic quinolinic acid (4)

The image above cites additional research linking depression with inflammation. 

Let’s Get Excited!

The next part of the inflammation-depression story involves the specialized immune cells of the brain called microglia. Microglial cells are our brains resident security force.  They sample the environment of the brain looking for threats, can take up different forms in order to respond to infections and repair damage to neurons once an infection is cleared or injury resolved.  Microglial cells produce chemical messengers that can cause inflammation and cell death - in order to quickly clear an infection like in the case of meningitis but can also produce nerve growth factors like BDNF, to protect and regenerate neurons once a threat has passed.  

Microglial cells can be activated by factors including infection (LPS and bacterial products as well as cytokines like Il-1/Il-6), certain metals (Co, Mn, Al, Hg), albumin/proteins and substances not normally found in the central nervous system (glyphosate) (5).  Once activated, microglial cells get to work spewing out reactive oxygen and nitrogen species which are like little chemical bombs used to destroy infected cells or pathogens, lipid peroxidation end products, which ramp up inflammation further call in other immune cells and  finally the neurotoxic glutamate, aspartate, and quinolinic acid, that must be degraded or removed from a synaptic space.  Glutamate and quinolinic acid exert their effects through binding to NMDA and other glutamate receptors in neurons.  Neurons work through creating and maintaining the concentrations of ions on either side of their cell membranes. When excessive glutamate binds to neurons it can cause excessive calcium influx into the cell.  In a healthy brain, there is sufficient mitochondrial energy to maintain these gradients and protect against the toxic effects of too much calcium within the cell or excessive glutamate stimulation.  In those exposed to environmental toxins, with poor lifestyle habits or in the aged, mitochondrial energy production is decreased, and neurons are more prone to damage by the release of neurotoxic agents by microglial cells. Further inflammation and reactive oxygen species damage glutamate transporters directly, worsening the problem.  It seems that this very process may underlie many neurodegenerative diseases.  In Alzheimer's dementia, for instance, we see mitochondrial dysfunction years before symptoms occur.  Mitochondria protect against the excitotoxicity that chronic microglial activation can cause.  Amyloid plaque is also associated with chronic inflammation and activated microglia, and it may be that the plaques seen in the brains of AD patients may be more a marker of the underlying inflammatory process- rather than a causative factor (9). Homocysteine also activates NMDA receptors, and AD patients are known to have high homocysteine levels.   This brings us back to ketamine. The pharmacology of ketamine involves blocking NMDA receptors.  It is the production of neurotoxic agents by microglial cells that damage neurons through binding NMDA receptors and causing calcium influx.  If the cell does not have enough energy to get rid of glutamate or pump calcium back out of the cell, it may be injured or perish.   The fact that ketamine is helpful for mood disorders strongly suggests it is not the only neuroinflammation but this process of NMDA receptor activation and excitotoxicity play a major role in how we feel.  Ketamine may spare neurons from the overactivation and damage caused by neurotoxic agents but too much NMDA antagonism results in an inability to form memories and dissociation.  It should be noted that glutamate is a very important primary excitatory neurotransmitter, involved in learning and brain plasticity.  Blocking glutamate neurotransmission using ketamine, unless in extreme circumstances is simply not practical and may not be safe for developing brains.  A better strategy would be to address sources of inflammation, such as stress, infections, and environmental toxicity in order to improve the outcome of people with depression. Ensuring adequate mitochondiral energy production wuld also be pertinent. 

The process of microglial activation can be very effective in clearing infection if it occurs and resolves quickly, after which the microglial cells go back to their resting stage.  The problem is again, chronic, unrelenting inflammation, that doesn't turn off.  With normal aging, a recent insult (trauma, infection, toxins)  or poor lifestyle, microglia become more intrinsically inflammatory. For instance, in several models of aging there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia (6).   Microglial cells in this state are said to be “primed” and will display prolonged and exaggerated inflammatory responses and result in more sickness behavior, depression and neuroinflammation if they are activated a second time.  This may explain “second impact syndrome” when a second (even mild) head injury occurring before an initial concussion has healed results in rapid and severe brain swelling and potentially catastrophic results.   A concussion or head trauma may prime microglial cells, if the resulting inflammation and resting state of the microglia is not resolved before a second trauma, excessive damage from the over zealous activation can occur (7).

Now what?

Now that we have identified another factor that contributes to depression let's discuss how we can mitigate or treat it.  The first step is as always, identifying the cause. Common causes of chronic inflammation include gut permeability (allowing LPS into bloodstream)  and allergenic foods (upregulate inflammation), chronic infections (dental, sinus etc), environmental toxins (pesticides, glyphosate, heavy metals), and stress.  

Beyond targeting neurotransmitters through supplementing precursors, enzyme cofactors or using drugs to modulate levels, what can we do?

1. Protection against inflammation:

  • Reduce Omega-6 fatty acids and trans fats (canola, corn oil, margarine, processed foods)
  • Five to 10 serving fruit and vegetables per day (polyphenol flavonoids epigenetically modulate inflammation).
  • Avoid excess sugar (shown to stimulate microglial activation)
  • Limit red meat, processed meats, and non grass fed, wild or free range animal products
  • Avoid MSG and sources of dietary glutamate, especially if inflammation already is present
  • Avoid sources of heavy metals (fish high on food chain, canned food, etc)
  • Consider turmeric or curcumin (inhibits inflam through nfKb)
  • Quercetin, silymarin and other flavonoids exert anti-inflammatory effects
  • EPA
  • Avoid food allergens
  • Vitamin D sufficient levels
  • Work to repair gut (SIBO and intestinal permeability may result in chronic leaking of LPS into bloodstream- this aggressively instigates an immune response)

2. Inhibit Microglial Activation Directly:

  • Ellagic Acid
  • Magnesium
  • Boswellia

3. Excitotoxicity Blockers:

  • Tetracycline antibiotics
  • Ketamine
  • Dextromethorphan
  • DHA
  • Magnesium

4. Reduce Glutaminase to lower Glutamate:

  • Blueberry extract
  • Silymarin
  • Curcumin

- Note this is very important to consider if giving supplemental glutamine. Inflammation upregulates the activity of glutaminase- watch for anxiety with supplemental glutamine 

5. Increase Cell Energy 

  • P5P/R5P
  • Niacinamide/NAD
  • Thiamine
  • COQ10
  • R-ALA
  • Acetyl-L-Carnitine/carnosine
  • Assess mold, and heavy metal toxicity as well as exposure to environmental pollutants like pesticides residues and solvents, that are mitochondrial toxins

6. If excitotoxicity suspected, consider Pyruvate (blocks excitotoxicty) or Butyrate or NAG >L Glutamine

A quick note about stress: Based on the results of a systemic review, psychosocial stress consistently led to elevated microglial activation in the hippocampus and other brain regions. Stress is an aetiological factor in depression, and new research suggests that stress (especially early life stress) actually primes microglial cells leading to a potentiated response and increase the chance of depression with additional stressors (8).

We know that high cortisol due to excessive psychosocial stress shrinks regions of the brain like the hippocampus, and now we can see a clear mechanism for this loss of volume.  Steps should be taken to mitigate stress- meditation, adequate movement, a practice of gratitude, and adaptogenic herbs may be of use. 

Stay tuned next week, for a discussion of Neuroinflammation/Excitotoxicity in ADD and Autism.