Neurotransmitters. Glutamate And MS- Is There A Connection ?
dr.vanta
Glutamate is a very important aminoacid for your health. It is found in abundance in the body, especially in the brain, gut and muscles. It is also a key neurotransmitter in the brain and gut. Healthy levels of glutamate are needed for optimal health. The problems occur when glutamate levels become too high- as it happens in MS and many other conditions.
Glutamate In The Brain
Glutamate In The Gut
Glutamate In The Muscles
Glutamate Effects On Oxidative Stress, Inflammation and Immune System
Glutamate And MS
Triggers/Factors That Increase Glutamate Levels/Disturb Glutamate Pathways
Natural Ways/Supplements To Improve Glutamate Levels- in THIS article
1.Glutamate In The Brain
Glutamate is the main excitatory neurotransmitter in the brain and spinal cord. It is made in the brain from glucose. The aminoacido glutamine is also a precursor of glutamate.
Let s look at Glutamine –>Glutamate–> GABA conversion:
Glutamine → Glutamate → GABA
↑ ↓
Citric Acid Cycle ← Succinate semialdehyde (SA)
High amounts of glutamate are found in the breast milk because it is essential for brain development.
In healthy amounts, glutamate has important roles — it facilitates the communication between different brain cells- neurons, astrocytes, oligodendrocytes (myelin producing cells) and microglia (which connect the nervous system with the immune system). Glutamate is involved in synaptic transmission of the nerve impulses, synaptic plasticity, brain development, learning, memory and sensory perception (how the brain receives and responds to the senses: hearing, vision, taste, smell, touch) and motor activity.
Too much glutamate however, becomes toxic to the brain creating a process called excitotoxicity. Excess glutamate disturbs the normal interaction between brain cells, and aggravate the autoimmune attack. It triggers a cascade of reactions leading to damage and death of the brain cells, brain inflammation (T cell mediated), as well as seizures, stroke, pain, decreased brain function and other symptoms. Too much glutamate also impairs the brain’s ability to regenerate (neurogenesis). These changes had been linked with MS, as well as stroke, Parkinson’s disease, Alzheimer’s, depression, epilepsy, migraines and even diabetes [1],[2],[3],[4],[5],[6],[7],[8],[9].
2.Glutamate In The Gut
Glutamate in healthy levels: Glutamate is the main gut energy source for gut cells, thus being involved in the absorption and metabolism for each nutrient in the GI tract. It plays a key role in digestion (improves digestive enzyme release, hormones, bowel movements and more), and also promotes the connection between gut and brain. Technical: In the oral cavity, glutamate from foods elicits umami taste, which is a signal for dietary protein ingestion in the brain [10]. Glutamate and its precursor, glutamine- help maintain healthy intestinal permeability, thus improving and/or preventing leaky gut [11],[12].
Excess glutamate: Glutamate is an important neurotransmitter in the gut (the enteric nervous system). Impaired glutamate pathways in the gut are associated with gastroesophageal reflux, irritable bowel disease and IBS. Digestive symptoms, inflammation and increased abdominal pain/ sensitivity also seem to be related to excess glutamate in the gut. It seems that the glutamate systems in the gut and brain are distinct (ie glutamate produced in the brain is used in the brain, and glutamate is produced in the gut stays in the gut [13]. However, keep in mind that the gut and brain are connected (gut- brain axis) and one system will influence the other.
3.Glutamate In The Muscles
Glutamate provides energy to muscle cells during exercise and boosts the production of glutathione [14]. Technical: sources of glutamate in the muscles: 1. actively taken up from the circulation 2.released by intracellular protein degradation 3.synthesized by transamination of the branched chain amino acids (especially leucine) [15]. Muscles respond quickly to abnormal (excessive) levels of glutamate.
Here is the perfect example showing how muscles are affected when there is too much glutamate and too little GABA: stiff person syndrome (SPS).
The enzyme glutamic acid decarboxylase (GAD) -which is responsible to convert glutamate to GABA is under autoimmune attack. The result: too much glutamate and GABA deficiency. Off note- stiff person syndrome (SPS) is misdiagnosed as MS or Parkinson’s because they share similar symptoms (and similar problem-excess glutamate and GABA deficiency). Symptoms of SPS affect mostly the muscles: fluctuating muscles spasms and rigidity (which progresses over time impairing mobility and walking) and abnormal postures. There is also increased sensitivity to stimuli (touch, noise, emotional stress), as well as similar MRI changes (brain lesions). This problem with GAD enzyme is not only characteristic to stiff person syndrome, but had been found in diabetes type 1 (both SPS and diabetes type I have a similar genetic predisposition- DQB1* 0201 allele), neurological diseases (ie epilepsy, cerebellar ataxia, myastenia gravis), and some cancers. SPS is treated with benzodiazepines, baclofen and rituximab [16],[17]- all of them used to treat MS, as well.
Too little glutamate is not good either. Low glutamate levels in the muscles had been linked with surgeries and trauma, as well as lung diseases (ie COPD) [18].
4.Glutamate Effects On Oxidative Stress, Inflammation and Immune System
Glutamate in healthy amounts: Glutamate, cysteine and glycine are the precursor amino acids for glutathione- the most abundant antioxidant found inside the cells. Glutamate has strong antioxidant and anti inflammatory qualities.
Glutamate has a strong impact on the T cells, the most important cells of the adaptive immune system, needed to fight infections and cancer.
Excess glutamate. What happens when glutamate levels become too high? It becomes pro-inflammatory, toxic and over stimulates the immune system -as seen in autoimmunity (MS, lupus, rheumatoid arthritis) [19].
5.Glutamate And MS
Glutamate could be considered a neurotransmitter responsible for multiple sclerosis symptoms. While changes in glutamate levels and glutamate receptor expression had been for a long time associated with late stages of MS, recent studies suggest that these changes develop early in MS. It seems that there is a problem with the enzymes responsible for the production and degradation of glutamate. Excess glutamate causes neuron and myelin damage. Myelin has two key functions: it protects the neuron and speeds up the electric impulses along the nerve fibers. When the myelin sheath breakdown, symptoms like double vision, muscle weakness, spasticity, problems with coordination, memory deficits develop.
Glutamate levels could be used as markers of MS, since studies found that glutamate levels are increased in the CSF (cerebrospinal fluid) during acute relapses of MS and in those with secondary progressive MS. Blood levels of glutamate had also been found higher in individuals with MS compared with healthy controls.
Technical: glutamine synthase and glutamate dehydrogenase (the enzymes responsible for the degradation of glutamate) are downregulated in MS white matter; in macrophages and microglia of the active lesions, glutaminase (the enzyme that produces glutamate) shows increased immunoreactivity. Effects of glutamate are mediated by a large family of glutamate receptors (GluRs): the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs), expressed by most/all cells of the nervous system, as well as by many non-neural cells in various organs and tissues[1],[2],[3],[4],[5],[6],[7].
6.Triggers/Factors That Increase Glutamate Levels/Disturb Glutamate Pathways
What are the trigger factors that disturb glutamate metabolism ? The main ones are:
energy deficiency
oxidative stress
mitochondrial dysfunction
abnormal calcium levels (calcium overload caused by excess glutamine had toxic effects on the neurons)
increased blood brain barrier and inflammation also aggravate the impairments along glutamate pathways
Technical: In gray matter, astrocytes take up synaptically released glutamate thus maintaining glutamate homeostasis. In white matter, oligodendrocytes appear to be the most important to promote glutamate clearance (oligodendrocytes also produce myelin). Astrocytes also help with glutamate clearance by converting it to glutamine. Glutamate receptor expression and glutamate removal are impaired in MS white matter, possibly mediated by TNFα.
Scientists believe now that an effective MS treatment would aim to decrease glutamate levels with drugs that influence glutamate pathways. This is not an easy task. In fact, I don’t see it done without significant side effects. That’s because drugs that target glutamate pathways could potentially get the levels of glutamate too low and create more problems (remember, glutamate has many functions, you need it in the brain). There is a lot of glutamate in the brain (glutamate in brain/spinal cord is almost a thousand-fold higher than other neurotransmitters and it can rise even higher).
Glutamate also converts into GABA, the relaxing, anti-anxiety neurotransmitter (which can be deficient in MS). More details here. Reducing glutamate levels would further aggravate GABA deficiency. Glutamate pathways are also very complex and linked with other neurotransmitters (serotonin, acetylcholine, dopa) in the brain and gut.
There are 3 drugs available that target glutamate or glutamate receptors:memantine, ketamine, and D-cylcoserine but carry significant risks. MS drugs Fingolimod and Glatiramer acetate seem to have a positive impact on glutamate levels, but they also have side effects [20],[21],[22],[23],[24].
