Glutamate is an excitotoxic amino acid, meaning it will kill brain cells when accumulated in quantity in interstitial tissue or elsewhere, or when ingested in quantity. And “quantity” would differ from individual to individual, “in quantity” being more than a healthy human needs for normal body function.
When present in protein or released from protein in a regulated fashion (through routine digestion) glutamate is vital for normal body function. It is the principal neurotransmitter in humans, carrying nerve impulses from glutamate stimuli to glutamate receptors throughout the body.
Glutamate becomes toxic only when present in greater quantity than a healthy human needs for normal body function. Then as an excitotoxic neurotransmitter, it fires repeatedly, damaging targeted glutamate-receptors and/or causing neuronal and non-neuronal death by over exciting those glutamate receptors until their host cells die (1-6).
It is well documented that free glutamate is implicated in kidney and liver disorders, neurodegenerative disease, and more. By 1980, glutamate-associated disorders such as headaches, asthma, diabetes, muscle pain, atrial fibrillation, ischemia, trauma, seizures, stroke, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington’s disease, Parkinson’s disease, depression, schizophrenia, obsessive-compulsive disorder (OCD), epilepsy, addiction, attention-deficit/hyperactivity disorder (ADHD), frontotemporal dementia and autism were on the rise, and evidence of the toxic effects of glutamate were generally accepted by the scientific community. A July 4, 2021 search of the National Library of Medicine using PubMed.gov returned 3971 citations for “glutamate-induced.”
The first study to address the possibility that glutamate from outside the body (from eating for example) might cause brain damage followed by obesity and reproductive dysfunction was published in 1969. At the time, researchers were administering glutamate to laboratory animals subcutaneously using Accent brand MSG because it had been observed that MSG was as effective for inflicting brain damage as more expensive pharmaceutical grade L-glutamate (7).
In the decade that followed, research confirmed that glutamate given as monosodium glutamate administered or fed to neonatal animals causes hypothalamic damage, endocrine disruption, and behavior disorders when given to immature animals after either subcutaneous (8-29) or oral (15,21,22,24,30-34) doses.
In the 1980s, researchers focused on identifying and understanding abnormalities associated with free glutamate, often for the purpose of finding drugs that would mitigate glutamate’s adverse effects. Researchers had confirmed that free glutamate was an excitotoxic amino acid which when consumed in controlled quantities is essential to normal body function as a neurotransmitters and building block of protein. But when accumulated in interstitial tissue in quantities greater than needed for normal body function (in excess), free glutamate became excitotoxic, firing repeatedly and killing brain cells.
1. Excitotoxicity and cell damage
https://www.sciencedaily.com/terms/excitotoxicity.htm (accessed 7/3/2021)
2. Belov Kirdajova D, Kriska J, Tureckova J, Anderova M. Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells. Front Cell Neurosci. 2020 Mar 19;14:51. doi: 10.3389/fncel.2020.00051.
3. Hernández DE et al. Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis. J. Cell Sci. 2018 Nov 19;131(22):jcs214684.
4. Garzón F et al. NeuroEPO preserves neurons from glutamate-induced excitotoxicity J. Alzheimers Dis. 2018;65(4):1469-1483.
5. Zárate SC, Traetta ME, Codagnone MG, Seilicovich A Reinés AG.
Humanin, a mitochondrial-derived peptide released by astrocytes, prevents synapse loss in hippocampal neurons. Front Aging Neurosci. 2019 May 31;11:123.
6. Plitman E et al. Glutamate-mediated excitotoxicity in schizophrenia: a review. Eur Neuropsychopharmacol. 2014;24:1591-1605.
7. Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science. 1969;164:719-721.
8. Olney, J.W. Ho, O.L., and Rhee, V. Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system. Exp Brain Res 14: 61-76, 1971.
11. Perez, V.J. and Olney, J.W. Accumulation of glutamic acid in the arcuate nucleus of the hypothalamus of the infant mouse following subcutaneous administration of monosodium glutamate. J Neurochem 19: 1777-1782, 1972.
13. Arees, E.A., and Mayer, J. Monosodium glutamate-induced brain lesions in mice. Presented at the 47th Annual Meeting of American Association of Neuropathologists, Puerto Rico, June 25-27, 1971. J Neuropath Exp Neurol31: 181, 1972. (Abstract)
17. Takasaki, Y. Studies on brain lesion by administration of monosodium L-glutamate to mice. I. Brain lesions in infant mice caused by administration of monosodium L-glutamate. Toxicology 9: 293-305, 1978.
18. Holzwarth-McBride, M.A., Hurst, E.M., and Knigge, K.M. Monosodium glutamate induced lesions of the arcuate nucleus. I. Endocrine deficiency and ultrastructure of the median eminence. Anat Rec 186: 185-196, 1976.
21. Burde, R.M., Schainker, B., and Kayes, J. Acute effect of oral and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rats. Nature(Lond) 233: 58-60, 1971.
23. Abraham, R., Doughtery, W., Goldberg, L., and Coulston, F. The response of the hypothalamus to high doses of monosodium glutamate in mice and monkeys: cytochemistry and ultrastructural study of lysosomal changes. Exp Mol Pathol 15: 43-60, 1971.
24. Burde, R.M., Schainker, B., and Kayes, J. Monosodium glutamate: necrosis of hypothalamic neurons in infant rats and mice following either oral or subcutaneous administration. J Neuropathol Exp Neurol 31: 181, 1972.
30. Olney, J.W., Ho, O.L. Brain damage in infant mice following oral intake of glutamate, aspartate or cystine. Nature(Lond) 227: 609-611, 1970.
34. Lemkey-Johnston, N., and Reynolds, W.A. Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate: a light and electron microscope study. J Neuropath Exp Neurol33: 74-97, 1974.