You may want to read first this article to better understand the functions of glutamate and how glutamate becomes toxic to the brain and promotes inflammation and autoimmunity.

I know many are looking for “glutamate blockers”. Rather than blocking glutamate, you actually need to improve its levels/ its pathways.

How To Improve Glutamate Levels/Glutamate Pathways 

  1. PPAR-γ Activators 

  2. Aminoacids : Taurine and NAC

  3. Probiotics

  4. Vitamins and Minerals : Vitamins: Bs, C, E, D, Magnesium, Lithium Orotate

  5. Lifestyle Changes/Therapies: Diet, Exercise, Sleep, Acupuncture

 

How To Improve Glutamate Levels

*GE =glutamate excitotoxicity

Glutamate is an essential (and the main excitatory) neurotransmitter in the brain. However, glutamate can become toxic- a process called glutamate excitotoxicity (GE)- in a few circumstances:if there is excess glutamate in the brain or the glutamate receptors are overstimulated. EC can also develop when the glutamate levels are normal but the glutamate receptors are over sensitive or when the glutamate pathways are impaired (ie problems with the enzymes, transporters, etc). GE plays a key role in neurodegeneration. Thus, researchers are looking into drugs and therapies focused on improving glutamate pathways to treat degenerative brain diseases. Technical: excessive activation of glutamate receptors by excitatory amino acids leads to a number of negative effects ie impairment of cellular calcium homeostasis, generation of free radicals, activation of the mitochondrial permeability transition and secondary GE [1].

Quick note: GE is also associated with depression, anxiety, autism, ADHD, chronic pain, strokes and brain tumors and many other conditions [2]. 

Improving glutamate levels/pathways can be a very complex task. Supplements, therapies and lifestyle changes that promote mitochondrial health, decrease oxidative stress and inflammation, balance glutamate with other neurotransmitters in the brain, and improve sugar and fat metabolism are all beneficial. Therefore, I looked at one thing that can achieve all these effects: PPAR-γ activators.

  1. PPAR-γ Activators 

In a nutshell, PPAR-γ activators can be one of the best way/therapy to counteract GE [3],[4]. PPARs(peroxisome proliferator-activated receptors) are specific proteins with profound effects on the body [5]. They belong to so called superfamily of nuclear receptors (other members of this class include vitamins A and D, estrogen thyroid and glucocorticoid receptors). There are 3 types of PPARs: PAR-a, PPAR-d, and PPAR-?.

PPAR-γ activators (agonists) can effectively protect against GE, decrease brain inflammation and degeneration.  Furthermore, they can “ reprogram” the immune response, stimulate metabolic and mitochondrial function, promote axon growth and make progenitor cells differentiate into myelinating producing cells (oligodendrocytes). PPAR-γ activators improve metabolism of sugars and fats, modulate the immune system and inflammation thus protecting against both autoimmunity and cancer. PPARs bind DNA and regulate gene expression [6],[7].

Many conditions, including MS had been associated with PPAR deficiencies. Treatment with PPAR-γ agonists was found to improve the viability of neurons and other brain cells, while reducing inflammation and oxidative stress [8]. I wrote here about the benefits of PPAR-γ agonists drugs for treating MS. Researchers believe that activating PPARs has a lot of therapeutic potential for MS. 

Prescriptions drugs that target these proteins (PPAR-γ agonists) are very powerful, but have a lot of side effects. In fact some of them had been withdrawn from the market. Rosiglitazone and Pioglitazone are PPAR-γ activators currently used for treating diabetes and insulin resistance (although are still on the marker, they do increase risk of heart attack and heart failure, as well as with an elevated risk of cardiovascular mortality).

You don’t need prescription drugs, as many herbs are supplements are natural PPAR-γ agonists. Although they have milder effects than the synthetic drugs (are partial PPAR γ agonists), you can still get a lot of benefits from using them.

  • Fish oil is my favourite and DHA seem to have stronger effects than EPA fatty acids [8],[9]. More details about fish oil in this article.

Many foods and herbs have the ability to decrease EC. They have multiple mechanisms of actions. One key reason why they work is because they are PPAR-γ activators. A review of scientific literature found that the following many natural herbs have potential to activate PPAR. (PPAR-γ -activating constituents in brackets, they are polyphenols). Some examples  :

  • Cannabis sativa L (THC)

  • Astragalus (Formononetin)

  • Green tea ((-)-Catechin)

  • Echinacea (Alkamides)

  • Palm oil (Tocotrienols)

  • Soya beans (Genistein, Daidezin)

  • Magnolia bark (Magnolol and Honokion)

  • Milk thistle (Sylimarin)

  • Licorice (multiple active ingredients)

  • Oregano (Biochanin A from dried leaves)

  • Thyme oil (Carvacrol)

  • Panax ginseng (Ginsenoside 20(S)-protopanaxatriol and ginsenoside Rb1 (in ginseng roots)

  • Chios Mastic Gum (Oleanonic acid)

  • Rosemary (Carnosic acid and Carnosol)

  • Sage (Carnosic acid and Carnosol)

  • Elderflowers(a-Linolenic acid, Linoleic acid, and Naringenin)

  • Red clover extracts (Isoflavones)

  • Grapes and win (Ellagic acid, Epicatechin gallate, Flavonoids)

  • Ginger root (6-Shogaol) [10]

Other natural compounds and herbs also activate PPAR-γ ? 

  • Curcumin [11] -very powerful. There are over 1500 papers examining the effects of curcumin alone. Supporting its powerful anti-inflammatory, anticancer, antioxidant, and an overall neuroprotectant effects [12]

  • Black seed oil [12]

  • Quercetin [13]

* in case of MS or other autoimmune conditions, supplements that overstimulate the immune system like echinacea, astragalus, ginseng and even green tea should be used cautiously or simply avoided

**Some aminoacids and nutrients described below are also activating PPARs.

2. Aminoacids : NAC and Taurine [14]. Both very important

3. Probiotics -various strains of Bifidobacteria and Lactobacilli species can counter GE [14]

4.Vitamins and Minerals

  • Vitamin B6 : can help decrease glutamate excess because is involved in the conversion glutamate to GABA. Vitamin B6 deficiency could be a reason why glutamate accumulates in excess and does not properly convert to GABA. Who is at risk to develop B6 deficiency ? Anyone with chronic illnesses, autoimmune diseases, malabsorption syndromes (ie celiac, IBD) and chronic alcohol intake. B6 deficiency does not occur alone, but usually combined with B12 and folate. Talking about dietary sources of B6: animal sources (organ meats,fish) are more bioavailable than vegetarian sources (potatoes, bananas). In supplement form, p-5-p is a good bioavailable form of B6 [15].

  • Vitamin B2 (riboflavin) is neuroprotective on its own and can counteract glutamate excess in a few different ways: helps improve mitochondrial function, fight oxidative stress and decrease inflammation. Riboflavin also activates vitamin B6. Technical: riboflavin-dependent enzymes have essential roles in pyridoxine activation, tryptophan-kynurenine pathway, and homocysteine metabolism [16].

  • Vitamin B12 (methylcobalamin) was also found to have protective effects against GE(technical: likely works by altering the membrane properties through SAM-mediated methylation) [17], [18].

  • Vitamin B9 (folic acid) supplementation: only in low doses. Glutamate is structurally similar to folic acid, it may compete for binding sites on neurons and may cause problems [19]. 

  • Vitamin D -either alone or in combination with prescription drug mementamine [20],[21]

  • Vitamin E [22]

  • CoQ10- ameliorates  glutamate excitotoxicity, mitochondrial function and oxidative stress [23]

  • Magnesium: I wrote the many benefits of magnesium here. This mineral (including in the magnesium acetyltaurate form) can help decreases GE  [24],[25]

  • Lithium orotate [26] and other trace minerals are all important for brain health and decrease GE

 

5. Lifestyle changes that activate PPARs and improve EC

  • I. Diet

Eat plenty of fresh vegetables- cruciferous vegetables and colorful veggies (yellow, red, orange, green, blue/purple). Add  spices, herbs to your foods (no limits, as much as you like).  Consume in moderation berries, pomegranate and citric fruits. A couple of cups of coffee daily are great too. Don’t forget about healthy fats from fish, nuts, seeds and avocados.  Technical: PPAR-? are activated by dietary fatty acids and their metabolites, working as lipid “sensors” that, upon activation, are able to significantly  improve the metabolism [28].

Polyphenols are a group of plant chemicals. Polyphenols can reduce GE, fight free radicals and decrease inflammation. There are over 500 different polyphenols divided in 4 main subgroups: flavonoids, phenolic acids, stilbenes and lignans. The best sources of polyphenols in foods include berries, pomegranate, calciferous and green leafy vegetables, nuts and seeds, herbs and spices, coffee, cacao, green tea and other herbal teas. Coffee and teas are the currently the major source of polyphenols in our diets[27]. Choose organic, from local farms, fresh if possible- as the content of polyphenols depends on how the food is grown, how is farmed and transported and whether is cooked or not.  Technical : Some polyphenols inhibit excitotoxicity by regulating intracellular calcium ion concentration, inhibiting glutamate receptors and increasing glutamate reuptake at the synapse.  Polyphenols reduce oxidative stress by acting as direct scavengers of free radicals and clearing superoxide and hydroxyl radicals and by raising the level of antioxidant enzymes ie glutathione peroxidase. Polyphenols can also chelate metal ions to prevent free radical formation, reduce inflammation by influencing transcription factors like NF-?B [29]. 

Dietary carbohydrates: everyone will have his/her unique needs for carbohydrates in the diet. Generally speaking the diet should be on the low carb side (some will need low amounts, while others will do better with moderate amount of carbs). Ketogenic diet had been found to decrease EC and activate PPARs, but may be not suitable for everyone. Caloric restriction, including intermittent fasting are also beneficial [ 30],[32],[32]. 

High carb diets and Western type diet certainly aggravate the impairments in sugar metabolism that are linked with EC and brain diseases. Virtually all processed and packed foods have added glutamate. Foods rich in glutamate include : soy sauce, hard cheeses, cured meats, grains (especially those with gluten), bone broth and beer. Glyphosate based herbicides [33] and GMO foods also seem to be dangerous and promote GE.

  • II.Exercise : many ways to improve brain health and GE. Here is one mechanism of action: BDNF suppresses glutamate excess [34] and one of the best way to raise BDNF is though exercise (especially very intense training like HIIT).

  • III.Acupuncture :Electroacupuncture can be very useful to manage neurodegeneration, being found to improve the blood flow of the brain, reduce oxidative stress,decrease glutamate excitotoxicity, maintain blood-brain barrier integrity and inhibit the death of the brain cells [35].

  • IV.Sleep well. Sleep apnea and sleep deprivation (including insomnia found in night shift workers) promote GE and death of brain cells, and also correlate with GABA deficiency [36],[37],[38],[39].

 

 

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