Summary
The brains and retinas of infant mice were examined following subcutaneous administration of monosodium glutamate (MSG) and structurally related compounds in an attempt to clarify the molecular specificity of MSG-induced neuropathology. Based on the effects on the infant retina and hypothalamus all compounds could be placed into one of four groups: 1. Those equipotent with L-MSG in necrosing neurons. 2. Those substantially more potent than L-MSG in necrosing neurons. 3. Those which affect non-neuronal components (glial, ependymal, Muller cells) without appreciable effects on neurons. 4. Those with no cytotoxic effects. Except for L-cysteine, all neurotoxic compounds were acidic amino acids known to excite neurones, the most potent neurotoxic compounds being those which are powerful neuroexcitants (N-methyl DL-aspartic and DL-homocysteic acids). The exception posed by L-cysteine may be more apparent than real in that the in vivo conversion of the SH terminal to a more acidic group (SO2H or SO3H) could account for its neurotoxicity. The close correspondence in molecular specificities associated with neurotoxic and neuroexcitatory properties of simple amino acids suggests the two phenomena may be governed by similar mechanisms of action.
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Adamo, N.J., Ratner, A.: Monosodium glutamate: Lack of effects on brain and reproductive function in rats. Science, N. Y. 169, 673–674 (1970).
Arees, E., Mayer, J.: Monosodium glutamate-induced brain lesions, electron microscopic examination. Science, N.Y. 170, 549–550 (1970).
—, Sandrew, B., Mayer, J.: MSG-induced optic pathway lesions in infant mice following sub-cutaneous injection. Fed. Proc. 30, 521 (1971).
Burde, R.M., Schainker, B., Kayes, J.: Monsodium glutamate: Acute effect of oral and subcutaneous administration on the arcuate nucleus of the hypothalamus in mice and rats. Nature (Lond.) 233, 58–60 (1971).
Cohen, A.I.: An electron microscopic study of the modification by monosodium glutamate of the retinas of normal and “rodless” mice. Amer. J. Anat. 120, 319–335 (1967).
Coulston, F.: In Report of National Academy of Science, National Research Council (United States) Food Protection Subcommittee on Monosodium Glutamate, pp. 24–25 (July, 1970).
Crawford, J.M.: The effect upon mice of intra-venticular injection of excitant and depressant amino acids. Biochem. Pharmacol. 12, 1443–1444 (1963).
Curtis, D.R.: Amino acid transmitters in mammalian central nervous systems. Proc. 4th Int. Cong. Pharm. 1, 9–31 (1969).
—, Crawford, J.M.: Central synaptic transmission-microelectro-phoretic studies. Ann. Rev. Pharmacol. 9, 209–240 (1969).
—, Watkins, J.C.: The excitation and depression of spinal neurons by structurally related amino acids. J. Neurochem. 6, 117–141 (1960).
—: Acidic amino acids with strong excitatory actions on mammalian neurons. J. Physiol. (Lond.) 166, 1–14 (1963).
—: The pharmacology of amino acids related to gamma-aminobutyric acid. Pharmacol. Rev. 17, 347–391 (1965).
Knittle, J.L., Ginsberg-Feller, F.: Cellular and metabolic alterations in obese rats treated with monosodium glutamate during the neonatal period. Bulletin Am. Peds. Soc. Gen. Meeting, Program Abstracts, pg. 6 (Apr. 1970).
Lucas, D.R., Newhouse, J.P.: The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch. Ophthal, N.Y. 58, 193–201 (1957).
Olney, J.W.: Glutamate-induced retinal degeneration in neonatal mice. Electron microscopy of the evolving lesion. J. Neuropath. exp. Neurol. 28, 455–474 (1969 a).
—: Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science, N.Y. 164, 719–721 (1969 b).
—: Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopy study. J. Neuropath. exp. Neurol. 30, 75–90 (1971 a).
—: Monosodium glutamate effects. Science, N.Y. 172, 294 (1971b).
Olney, J.W., Ho, O.L.: Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature (Lond.) 227, 609–610 (1970).
—, Sharpe, L.G.: Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science, N.Y. 166, 386–388 (1969).
Oser, B.L., Carson, S., Vogin, E.E., Cox, G.E.: Oral and subcutaneous administration of monosodium glutamate to infant rodents and dogs. Nature (Lond.) 229, 411–413 (1971).
Potts, A.M., Modrell, K.W., Kingsbury, C.: Permanent fraotionation of the electroretinogram by sodium glutamate. Amer. J. Ophthal. 50, 900–907 (1960).
Redding, T.W., Shally, A.V.: The effects of MSG on the endocrine axis in rats. Fed. Proc. 29, 755 (1970).
Redding, T.W., Shally, A.V., Arimura, A., Wakaboyashi, I.: Effect of monosodium glutamate on some endocrine functions. Neuroendocrinology (in press) (1971).
Sprince, H.C., Joseph, J., Magazino, J.: Convulsant activity of homoeysteine and other short-chain mercaptoacids: Protection therefrom. Ann. N.Y. Acad. Sci. 166, 323–325 (1969).
Takao, T., Kanazawa, A.: Isolation of L-a amino adipic acid from hog liver. Biochim. biophys. Acta (Amst.) 117, 490–492 (1966).
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Supported in part by PHS grants MH 38894 (Research Career Development Award to John W. OIney) and NS 09156. We thank Dr. E. Robins for suggestions in preparation of the manuscript.
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Olney, J.W., Ho, O.L. & 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). https://doi.org/10.1007/BF00234911
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DOI: https://doi.org/10.1007/BF00234911