Processed free glutamic acid kills brain cells
(produces brain lesions)
in experimental animals
In Animals Other than Primates
In the late 1960s, Olney (1) became suspicious that obesity in mice, which was observed after neonatal mice were treated with glutamic acid (GLU) for purposes of inducing and studying retinal pathology, might be associated with hypothalamic lesions caused by GLU treatment; and in 1969 he first reported that GLU treatment did indeed cause brain lesions, particularly acute neuronal necrosis in several regions of the developing brain of neonatal mice, and acute lesions in the brains of adult mice given 5 to 7 mg/g of GLU (milligrams of GLU per gram of animal body weight) subcutaneously.(1)
Research which followed confirmed that GLU, which is usually given as the sodium salt, MSG, induces hypothalamic damage when given to immature animals after either subcutaneous (2-23) or oral (9,15-16,18,24-28) doses.
Work by Lemkey-Johnston and Reynolds(28) published in 1974 included an extensive review of the data on brain lesions in mice. They confirmed the phenomenon of GLU induced neuro-toxicity; described the sequence of the lesions; and emphasized the critical aspects of species variation, developmental age, route of administration, time of examination of brain material after insult, and thoroughness of tissue sampling methods. A review of GLU induced neurotoxicity, published by Olney in 1976(29), mentioned species (immature mice, rats, rabbits, guinea pigs, chicks, and rhesus monkeys) demonstrating GLU induced neurotoxicity, and efficiency of both oral and subcutaneous administration of GLU in producing acute neuronal necrosis; discussed the nature and extent of the damage done by GLU administration and the impact of GLU administration to GLU levels in both brain and blood; and discussed the similar neurotoxic effects of a variety of acidic structural analogues.
In Sub-Human Primates
Studies of sub-human primates (3,16) were felt to be particularly meaningful to the study of GLU toxicity, particularly because GLU toxicity found in laboratory animals might be relevant to humans. As early as 1969, Olney had suggested that GLU could be involved in the unexplained brain damage syndromes occurring in the course of human ontogenesis.(3) Olney demonstrated that the infant rhesus monkey (Macaca mulatta) is susceptible to GLU-induced brain damage when administered a high dose (2.7g GLU/kg of body weight) subcutaneously.(3)
Olney et al.(16) expanded Olney's earlier work(3) with a study of eight
additional infant rhesus monkeys and, using light microscopy and the electron
microscope, reconfirmed Olney's earlier findings(3) of hypothalamic lesions,
and discussed the findings of both Abraham et al.(17) and Reynolds et al.(30)
who had questioned his work. Olney found his data to be entirely consistent
with studies done previously by his own and other laboratories on all species
of animals tested.
1. Olney, J.W. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164: 719-721, 1969.
2. 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.
3. Olney, J.W., and Sharpe, L.G. Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science 166: 386-388, 1969.
4. Snapir, N., Robinzon, B., and Perek, M. Brain damage in the male domestic fowl treated with monosodium glutamate. Poult Sci 50: 1511-1514, 1971.
5. 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.
6. Arees, E.A., and Mayer, J. Monosodium glutamate-induced brain lesions: electron microscopic examination. Science 170: 549-550, 1970.
7. 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 Neurol 31: 181, 1972. (Abstract)
8. Everly, J.L. Light microscopy examination of monosodium glutamate induced lesions in the brain of fetal and neonatal rats. Anat Rec 169: 312, 1971.
9. Olney, J.W. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. J Neuropathol Exp Neurol 30: 75-90, 1971.
10. Lamperti, A., and Blaha, G. The effects of neonatally-administered monosodium glutamate on the reproductive system of adult hamsters. Biol Reprod 14: 362-369, 1976.
11. 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.
12. 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.
13. Holzwarth-McBride, M.A., Sladek, J.R., and Knigge, K.M. Monosodium glutamate induced lesions of the arcuate nucleus. II Fluorescence histochemistry of catecholamines. Anat Rec 186: 197-205, 1976.
14. Paull, W.K., and Lechan, R. The median eminence of mice with a MSG induced arcuate lesion. Anat Rec 180: 436, 1974.
15. 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.
16. Olney, J.W. Sharpe, L.G., Feigin, R.D. Glutamate-induced brain damage in infant primates. J Neuropathol Exp Neurol 31: 464-488, 1972
17. 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.
18. 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.
19. Robinzon, B., Snapir, N., and Perek, M. Age dependent sensitivity to monosodium glutamate inducing brain damage in the chicken. Poult Sci 53: 1539-1942, 1974.
20. Tafelski, T.J. Effects of monosodium glutamate on the neuroendocrine axis of the hamster. Anat Rec 184: 543-544, 1976.
21. Coulston, F. In: Report of NAS,NRC, Food Protection Subcommittee on Monosodium Glutamate. July, 1970. pp
22. Inouye, M. and Murakami, U. Brain lesions and obesity in mouse offspring caused by maternal administration of monosodium glutamate during pregnancy. Congenital Anomalies 14: 77-83, 1974.
23. Olney, J.W., Rhee, V. and DeGubareff, T. Neurotoxic effects of glutamate on mouse area postrema. Brain Research 120: 151-157, 1977
24. 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.
25. Lemkey-Johnston, N., and Reynolds, W.A. Incidence and extent of brain lesions in mice following ingestion of monosodium glutamate (MSG). Anat Rec 172: 354, 1972.
26. Takasaki, Y. Protective effect of mono- and disaccharides on glutamate-induced brain damage in mice. Toxicol Lett 4: 205-210, 1979.
27. Takasaki, Y. Protective effect of arginine, leucine, and preinjection of insulin on glutamate neurotoxicity in mice. Toxicol Lett 5: 39-44, 1980.
28. 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 Neurol 33: 74-97, 1974.
29. Olney, J. W. Brain damage and oral intake of certain amino acids.
In: Transport Phenomena in the Nervous System: Physiological and Pathological
Aspects Levi, G., Battistin, L., and Lajtha, A. Eds. New York:
Plenum Press, 1976.
also Advances in Experimental Medicine and Biology 69: 497-506, 1976.
30. Reynolds, W.A., Lemkey-Johnston, N., Filer, L.J. Jr., and Pitkin,
R.M. Monosodium glutamate: absence of hypothalamic lesions after ingestion
by newborn primates. Science 172: 1342-1344, 1971.
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