Glutamate Excitotoxicity: The Brain, The Nervous System & Nutritional Solutions

Glutamate is an excitatory neurotransmitter. Glutamate is an important neurotransmitter for learning, cognitive function and memory. However, there are many problems that can arise when glutamate metabolism is out of balance. In fact, a number of neuro-degenerative conditions feature glutamate "excitotoxicity".

Emerging scientific research has not only identified glutamate excitotoxicity as a core etiology in numerous degenerative conditions, an emerging body of literature also demonstrates the potent neuro-protective effects of certain nutritional herbs and botanicals. These neuro-protective effects have shown to protect against the cascade of glutamate-induced excitotoxicity, and the subsequent neuronal cell death that ensues.

A growing list of neuro-degenerative conditions exist, which have shown to feature glutamate excitotoxicity. Some of these include:

  • Alzheimer's (1)
  • Brain trauma and brain injury (2)
  • ALS (3)
  • Multiple sclerosis (4)
  • Seizure disorders (5)
  • Parkinson's (6)
  • Stroke & Ischemia (7)
  • Autism (8)
  • Huntington's
  • Schizophrenia

As a neurotransmitter, glutamate is actually one of the most abundant molecules in the brain. Under normal circumstances, glutamate gets converted into the inhibitory neurotransmitter GABA. The gene/enzyme most responsible for this reaction appears to be GAD1 (glutamate decarboxylase). GAD1 uses the B-vitamin, P5P (Vitamin B-6) as the cofactor for this conversion. Deficiency of GAD1 enzyme activity is known to lead to a condition known as "Pyridoxine-dependent epilepsy" (9, 10). It seems plausible that this type of epilepsy strongly features glutamate overload and GABA deficiency.

A lesser known, but important role of glutamate is in nitrogen removal. The resultant reaction of the glutamate dehydrogenase enzyme is to release ammonia. Ammonia, which itself is neurotoxic, must be converted into urea in the liver. If there are problems with the urea cycle, and the ammonia to urea conversion, ammonia builds up and can lead to a list of serious symptoms, such as: seizures, hyperventilation, lethargy and vomiting. Seeking the source of ammonia toxicity should definitely account for possible glutamate overload (11).

Methylation Cycle Support & Glutamate

With all of the craze surrounding the use of 5 methyltetrahydrofolate (5-MTHF) supplementally to bypass certain MTHFR gene mutations, it should be pointed out the frequency of adverse reactions to methylfolate supplementation is rather common. Among the primary adverse reactions to methylfolate are symptoms of: anxiety, mania, aggression, and headaches. Why?

Folates, also known as Vitamin B-9 are of different forms. Some of these include: Folinic acid (5-formyl tetrahydrofolate), Folic acid, 10-formyl tetrahydrofolate and 5 methyl tetrahydrofolate. Folates are comprised of numerous glutamic acids conjugates. The higher the dose of folates, the greater the propensity towards an increase in the pool of free glutamate. Hence, the "excitatory" and neurological types of adverse effects of folate in certain individuals.

Additionally, folate (in the form of tetrahydrofolate) is a cofactor in the conversion of the amino acid histidine into glutamic acid. The compound FIGLU (formiminoglutamate) is the intermediate in this reaction (12). This is why elevated urinary FIGLU is an indicator of a folate deficiency.

Free Practitioner Training Webinar - Diving Deep Into Functional Lab Test Analysis. Learn how to pair functional lab tests to create effective protocols.

Glutamate & The Immune System

One of the key mechanisms of glutamate-induced neuronal cell injury is in the release of glutamate by microglial cells (13, 14). Microglial cells are essentially the resident immune cells of the brain and nervous system. It is essential to understand the connection between the nervous system and the immune system. The release of glutamate by microglia serves as one key link.

Once the free pool of glutamate increases, glutamate receptors, such as NMDA are over-stimulated. This then causes a massive influx of calcium ions into cells, resulting in neuronal cell damage, and cell death.

Numerous factors can function as inducers of microglial activation. Mercury toxicity has shown to rapidly induce microglial activation (15, 16), and mercury toxicity has shown to alter the transport and uptake of glutamate in mouse brain (17). The toxic metal, cadmium has also shown a strong ability to induce microglial activation (18).

Essentially any type of "non-self" molecule is capable of setting off microglial activation in brain and neuronal tissue. This is inclusive of various pathogens and antigens, viruses, vaccines, adjuvants, and any foreign substance that crosses the blood-brain barrier.

Nutritional Targets For Neuro-Protection

While the search for drugs to attenuate and prevent neuronal cell degeneration has been in place for many years, a number of nutritional and botanical approaches are promising and effective.

Before reviewing possible nutritional and botanical therapies, it is first essential to understand the glutamate receptors. There are 2 different classes of glutamate receptors: ionotropic and metabotropic. Both types of receptors use various ions to accomplish transmission, but the ionotropics tend to be more rapid in relaying signaling.

Of the 3 different ionotropics, in terms of excitotoxicity, the NMDA (n-methyl d-aspartic acid) receptor has received the most attention. When the free pool of glutamate increases (and potentially other types of excitotoxins as well), the NMDA receptor gets over-loaded, resulting in a massive influx of calcium ions. This excitotoxic cascade then triggers various inflammatory and cell-destructive enzyme reactions, resulting in neurotoxicity and cell death.

Zinc picolinate has shown some neuro-protective effects, but primarily against the excitotoxic effects of quinolinic acid, but not glutamate (19).

A large group of botanicals have shown specific neuro-protective actions, including NMDA antagonist capabilities, inhibition of calcium channel influx, as well as inhibition of cell programed death.

  • Constituents of Cat's Claw (uncaria tomentosa) - have shown to possess NMDA inhibitive qualities
  • Lycopodii Serrati (Jin Bu Huan, or Chinese Club Moss) - possesses potent NMDA-inhibitive actions (20, 21)
  • Radix Polygalae (Yuan Zhi) -  reduces microglial inflammation, reduces excitotoxicity-related cell death, sedative effects, contains tenuifolin, which inhibits beta amyloid peptides (associated with Alzheimer's) (22, 23)
  • Ramulus Uncariae cum Uncis (Gou teng or Uncaria rhynchophylla) - NMDA inhibitor, used traditionally for convulsive disorders in Chinese medicine (24)
  • Gastrodia rhizome  - Reduces NMDA release, increases GABA induction, reduce excitotoxicity. Used in Traditional Chinese medicine to treat stroke, epilepsy, dementia (25, 26)
  • Radix Glycyrrhizae (Licorice root) - inhibits calcium channel excitotoxic response, inhibition of apoptosis (cell-programmed death) (28)
  • Radix Ginseng (Ginseng root) - Block NMDA-induced current, inhibits calcium influx, contains neuro-protectant notoginsenoside, reduction in excitotoxicity-related cell death (27)
  • Gingko biloba - Neuro-protectant, contains NMDA-inhibitors such as Bilobalide, protects from Ischemic brain injury, potent antioxidant effects (29, 30, 31)
  • Radix Scrophulariae (common carpet beetle, Xuan shen) - Inhibits calcium response, reduction in ROS's, protects against excitotoxicity-related cell death (32)

It is important to address that the above discussed botanicals have been used in Traditional Chinese medicine systems for hundreds, or possibly thousands of years. Recent scientific research has extensively investigated the constituent properties of these herbs, as well as their chemical effects on glutamate excitoxicity, and the associated neurotoxic cascades.

The implementation of any botanical is best done under proper guidance through an herbalist with the necessary skill set, for pairing herbs for the individual in question. In this way, one is able to determine the best uses of certain herbal formulations.

If you would like to speak with Michael and Julie regarding your health & nutrition needs, or to schedule a private consultation, please contact us here.