Experimental Brain Research

, Volume 14, Issue 1, pp 61–76 | Cite as

Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system

  • J. W. Olney
  • Oi Lan Ho
  • V. Rhee
Article

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.

Key words

Cytotoxic Amino Acids Infant CNS Glutamate 

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References

  1. Adamo, N.J., Ratner, A.: Monosodium glutamate: Lack of effects on brain and reproductive function in rats. Science, N. Y. 169, 673–674 (1970).Google Scholar
  2. Arees, E., Mayer, J.: Monosodium glutamate-induced brain lesions, electron microscopic examination. Science, N.Y. 170, 549–550 (1970).Google Scholar
  3. —, Sandrew, B., Mayer, J.: MSG-induced optic pathway lesions in infant mice following sub-cutaneous injection. Fed. Proc. 30, 521 (1971).Google Scholar
  4. 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).Google Scholar
  5. 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).Google Scholar
  6. 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).Google Scholar
  7. Crawford, J.M.: The effect upon mice of intra-venticular injection of excitant and depressant amino acids. Biochem. Pharmacol. 12, 1443–1444 (1963).Google Scholar
  8. Curtis, D.R.: Amino acid transmitters in mammalian central nervous systems. Proc. 4th Int. Cong. Pharm. 1, 9–31 (1969).Google Scholar
  9. —, Crawford, J.M.: Central synaptic transmission-microelectro-phoretic studies. Ann. Rev. Pharmacol. 9, 209–240 (1969).Google Scholar
  10. —, Watkins, J.C.: The excitation and depression of spinal neurons by structurally related amino acids. J. Neurochem. 6, 117–141 (1960).Google Scholar
  11. —: Acidic amino acids with strong excitatory actions on mammalian neurons. J. Physiol. (Lond.) 166, 1–14 (1963).Google Scholar
  12. —: The pharmacology of amino acids related to gamma-aminobutyric acid. Pharmacol. Rev. 17, 347–391 (1965).Google Scholar
  13. 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).Google Scholar
  14. 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).Google Scholar
  15. 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).Google Scholar
  16. —: Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science, N.Y. 164, 719–721 (1969 b).Google Scholar
  17. —: Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopy study. J. Neuropath. exp. Neurol. 30, 75–90 (1971 a).Google Scholar
  18. —: Monosodium glutamate effects. Science, N.Y. 172, 294 (1971b).Google Scholar
  19. 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).Google Scholar
  20. —, Sharpe, L.G.: Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science, N.Y. 166, 386–388 (1969).Google Scholar
  21. 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).Google Scholar
  22. Potts, A.M., Modrell, K.W., Kingsbury, C.: Permanent fraotionation of the electroretinogram by sodium glutamate. Amer. J. Ophthal. 50, 900–907 (1960).Google Scholar
  23. Redding, T.W., Shally, A.V.: The effects of MSG on the endocrine axis in rats. Fed. Proc. 29, 755 (1970).Google Scholar
  24. Redding, T.W., Shally, A.V., Arimura, A., Wakaboyashi, I.: Effect of monosodium glutamate on some endocrine functions. Neuroendocrinology (in press) (1971).Google Scholar
  25. 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).Google Scholar
  26. Takao, T., Kanazawa, A.: Isolation of L-a amino adipic acid from hog liver. Biochim. biophys. Acta (Amst.) 117, 490–492 (1966).Google Scholar

Copyright information

© Springer-Verlag 1971

Authors and Affiliations

  • J. W. Olney
    • 1
  • Oi Lan Ho
    • 1
  • V. Rhee
    • 1
  1. 1.Department of PsychiatryWashington University School of MedicineSt. LouisUSA

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