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Spinal neuronal pathology associated with continuous intrathecal infusion ofN-methyl-d-aspartate in the rat

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Summary

Continuous intrathecal infusion ofN-methyl-d-aspartate (NMDA) at the level of the lumbar enlargement of the spinal cord in middle-aged rats produced dose-dependent toxicity of spinal cord neuronal systems. Toxicity was enhanced by coadministration of glycine, but was significantly reduced when NMDA was coadministered with the competitive inhibitordl-2-amino-5-phosphovaleric acid or the noncompetitive inhibitor MgSO4. The toxic effects of NMDA were manifest most dramatically and at the lowest concentrations in the neuropil, while neuronal loss was obvious at higher concentrations. The distribution and intensity of reactive astrocytosis was consistent with the known regional and subcellular distribution of NMDA receptors in the spinal cord of rats. The increase in ribosomes and rough endoplasmic reticulum observed in anterior horn cells suggested an increase of cell metabolism reflecting either a nonspecific response to injury or a specific increase in cell metabolism secondary to sustained activation of NMDA receptors. The present studies implicate excitatory amino acid receptors of the NMDA type in producing toxicity to selected neuronal populations of the spinal cord. This model provides a system for studies of the protective effects and rescue of neuronal populations susceptible to the toxic effects of excitatory amino acids.

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References

  1. Ascher P, Nowak L (1987) Elecrophysiological studies of NMDA receptors. Trends Neurosci 10:284–288

    Google Scholar 

  2. Birch PJ, Grossman CJ, Hayes AG (1988) Kynurenic acid antagonizes responses to NMDA via an action at the strychnineinsensitive glycine receptor. Eur J Pharmacol 154:85–87

    Google Scholar 

  3. Choi D (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379

    Google Scholar 

  4. Cotman CW, Iversen LL (1987) Excitatory amino acids in the brain—Focus on NMDA receptors. Trends Neurosci 10:263–265

    Google Scholar 

  5. Cotman CW, Monaghan DT, Ottersen OP, Storm-Mathisen J (1987) Anatomical organisation of excitatory amino acid receptors and their pathways. Trends Neurosci 10:273–280

    Google Scholar 

  6. Curtis DR, Phillis JW, Watkins JC (1959) Chemical excitation of spinal neurons. Nature 183:611–612

    Google Scholar 

  7. Fagg GA, Foster AC, Ganong AH (1986) Excitatory aminoacid synaptic mechanism and neurological function. Trends Pharmacol Sci 7:357–363

    Google Scholar 

  8. Farber JL (1981) The role of calcium in cell death. Life Sci 29:1289–1295

    Google Scholar 

  9. Farber JL (1982) Biology of disease: membrane injury and calcium homeostasis in the pathogenesis of coagulative necrosis. Lab Invest 47:114–123

    Google Scholar 

  10. Farber JL, Chien KR, Mittnacht S Jr (1981) Myocardial ischemia: the pathogenesis of irreversible cell injury in ischemia. Am J Pathol 102:271–281

    Google Scholar 

  11. Fonnum F (1984) Glutamate: a neurotransmitter in mammalian brain. J Neurochem 42:1–11

    Google Scholar 

  12. Jahr CE, Yoshioka K (1986) Ia afferent excitation of motoneurones in the in vitro new-born rat spinal cord is selectively antagonized by kynurenate. J Physiol 370:515–530

    Google Scholar 

  13. Jeftinija S (1989) Excitatory transmission in the dorsal horn is in part mediated through APV-sensitive NMDA receptors. Neurosci Lett 96:191–196

    Google Scholar 

  14. Jessell TM, Yoshioka K, Jahr CE (1986) Amino acid receptormediated transmission at primary afferent synapses in rat spinal cord. J Exp Biol 124:239–258

    Google Scholar 

  15. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531

    Google Scholar 

  16. Kemp JA, Foster AC, Wong EHF (1987) Non-competitive antagonists of excitatory amino acid receptors. Trends Neurosci 10:294–298

    Google Scholar 

  17. Kessler M, Terramani T, Lynch G, Baudry M (1989) A glycine site associated withN-methyl-d-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 52:1319–1328

    Google Scholar 

  18. Loomis CW, Milne B, Cervenko FW (1987) Determination of cross-tolerance in rat spinal cord using intrathecal infusion via sequential mini osmotic pumps. Pharmacol Biochem Behav 26:131–139

    Google Scholar 

  19. MacDermott AB, Dale N (1987) Receptors, ion channels and synaptic potentials underlying the integrative actions of excitatory amono acids. Trends Neurosci 10:280–284

    Google Scholar 

  20. Monaghan DT, Cotman CW (1986) Distribution ofN-methyl-aspartate-sensitivel-[3H] glutamate-binding sites in rat brain. J neurosci 5:2909–2919

    Google Scholar 

  21. Nag S (1986) Cerebral endothelial plasma membrane alterations in acute hypertension. Acta neuropathol (Berl) 70:38–43

    Google Scholar 

  22. Ogawa M, Araki M, Nagatsu I, Yoshida M (1989) Astroglial cell alteration caused by neurotoxins: immunohistochemical observations with antibodies to glial fibrillary acidic protein, laminin, and tyrosine hydroxylase. Exp Neurol 106:187–196

    Google Scholar 

  23. Olney JW, Price MT, Samson L, Labruyere J (1986) The role of specific ions in glutamate neurotoxicity. Neurosci Lett 65:65–71

    Google Scholar 

  24. Olney JW, Price MT, Fuller TA, Labruyere J, Samson L, Carpenter M, Mahan K (1986) The anti-excitotoxic effects of certain anesthetics, analgesics and sedative-hypnotics. Neurosci Lett 68:29–34

    Google Scholar 

  25. Pisharodi M, Nauta HJW (1985) An animal model for neuronspecific spinal cord lesions by the microinjection ofN-methylaspartate, kainic acid, and quisqualic acid. Appl Neurophysiol 48:226–233

    Google Scholar 

  26. Pole P (1987) NMDA receptors mediate background and excessive activity of gamma-motorneurones in the spinal cord. Eur J Pharmacol 144:113–115

    Google Scholar 

  27. Rothman SM, Olney JW (1987) Excitotoxicity and the NMDA receptor. Trends Neurosci 10:299–302

    Google Scholar 

  28. Rothman SM, Thurston JH, Hauhart RE (1987) Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience 22:471–480

    Google Scholar 

  29. Schneider SP, Perl ER (1988) Comparison of primary afferent and glutamate excitation of neurons in the mammalian spinal dorsal horn. J Neurosci 9:2062–2073

    Google Scholar 

  30. Simon RP, Swan JH, Griffiths T, Meldrum BS (1984) Blockade ofN-methyl-d-aspartate receptors may protect against ischemic damage in the brain. Science 226:850–852

    Google Scholar 

  31. Urca G, Raigorodsky G (1988) Behavioural classification of excitatory amino acid receptors in mouse spinal cord. Eur J Pharmacol 153:211–220

    Google Scholar 

  32. Watkins JC, Olverman HJ (1987) Agonists and antagonists for excitatory amino acid receptors. Trends Neurosci 10:265–272

    Google Scholar 

  33. Wieloch T (1985) Hypoglycemia-induced neuronal damage prevented by anN-methyl-d-aspartate antagonist. Science 230:681–683

    Google Scholar 

  34. Wilcox GL (1988) Pharmacological studies of grooming and scratching behaviour elicited by spinal substance P and excitatory amino acids. Ann NY Acad Sci 525:228–236

    Google Scholar 

  35. Zochodne DW, Bolton CF, Wells GA, Gilbert JJ, Hahn AF, Brown JD, Sibbald WA (1987) Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 110:819–842

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology (Neuropathology), Queen's University, K7L 3N6, Kingston, Ontario, Canada

    S. Nag

  2. Department of Medicine (Neurology), Queen's University, K7L 3N6, Kingston, Ontario, Canada

    R. J. Riopelle

  3. Kingston General Hospital, K7L 3N6, Kingston, Ontario, Canada

    R. J. Riopelle

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  1. S. Nag
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  2. R. J. Riopelle
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Supported by the ALS Society of Canada

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Nag, S., Riopelle, R.J. Spinal neuronal pathology associated with continuous intrathecal infusion ofN-methyl-d-aspartate in the rat. Acta Neuropathol 81, 7–13 (1990). https://doi.org/10.1007/BF00662631

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  • DOI: https://doi.org/10.1007/BF00662631

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