Summary
There is increasing evidence that the neurotoxic effects of excitatory amino acids and their analogues are part of the pathogenesis of neuronal degeneration in acute and chronic neurological disease. Recent studies indicate that activation of excitatory amino acid receptors is also induced in the mechanism of neuronal damage induced by impairment of cellular energy metabolism. This article briefly summarizes the evidence for the presence of such a mechanism and discusses metabolic diseases in which excitatory amino acids alone or in combination with energy deficiency could play a pathogenetic role. In these and other metabolic diseases, antagonists to excitatory amino acid receptors may offer a therapeutic opportunity; however, there are potential limits that may prevent chronic use.
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References
Amir N, Elpeleg RN, Joseph A, Soffer D (1992) Glutaric aciduria type I: Correlation between neuroradiological features and pathological findings.Abstracts of the 30th Annual Symposium of SSIEM, P86.
Balcar VJ, Johnston GAR (1972) The structural specificity of the high affinity uptake ofl-glutamate andl-aspartate by rat brain slices.J Neurochem 19: 2657–2666.
Barnes JM, Henley JM (1992) Molecular characteristics of excitatory amino acid receptors.Progr Neurobiol 39: 113–133.
Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?Ann Neurol 31: 119–130.
Beal MF, Swartz KJ, Hyman BT, Storey E, Finn SF, Koroshetz W (1991) Aminooxyacetic acid results in excitotoxin lesions by a novel indirect mechanism.J Neurochem 57: 1068–1073.
Bennett JP, Logan WJ, Snyder SH (1973) Amino acids as central nervous transmitters: The influence of ions, amino acid analogues, and ontogeny on transport systems forl-glutamic and aspartic acids and glycine into central nervous synaptosomes of the rat.J Neurochem 21: 1533–1550.
Bremer HJ, Duran M, Kamerling JP, Przyrembel H, Wadman SK (1981)Disturbances of Amino Acid Metabolism: Clinical Chemistry and Diagnosis. Baltimore-Munich: Urban & Schwarzenberg.
Brown GK, Scholem RD, Croll HB, Wraith JE, McGill JJ (1989) Sulfite oxidase deficiency: clinical, neuroradiologic, and biochemical features in two new patients.Neurology 39: 252–257.
Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic cell death.Annu Rev Neurosci 13: 171–182.
Cox DWG, Headley MH, Watkins JC (1977) Actions ofl-andd-homocysteate in rat CNS: a correlation between low-affinity uptake and the time courses of excitation by microelectrophoretically appliedl-glutamate analogues.J Neurochem 29: 579–588.
Garcia-Castro J-M, Isales-Forsythe CM, Levey HL et al (1982) Prenatal diagnosis of non-ketotic hyperglycinemia.N Engl J Med 306: 79–81.
Henneberry RC, Novelli A, Cox JA, Lysko PG (1989) Neurotoxicity at theN-methyl-d-aspartate receptor in energy-compromised neurons: An hypothesis for cell death in aging and disease.Ann NY Acad Sci 568: 225–233.
Heyes MP (1987) Hypothesis: A role for quinolinic acid in the neuropathology of glutaric aciduria type I.Can J Neurol Sci 14: 441–443.
Jahr L, Lester RA (1992) Synaptic excitation mediated by glutamate-gated ion channels.Curr Opin Neurobiol 2: 270–274.
Kaku DA, Goldberg MP, Choi DW (1992) Antagonism of non-NMDA receptors augments the neuroprotective effect of NMDA receptor blockade in cortical cultures subjected to prolonged deprivation of oxygen and glucose.Brain Res 554: 344–347.
Knopfel T, Zeise ML, Cuenod M, Zieglgansberger W (1987)l-Homocysteic acid but notl-glutamate is an endogenousN-methyl-d-aspartic acid preferring agonist in rat neocortical neurons in vitro.Neurosci Lett 81: 188–192.
Koh, J-Y, Palmer E, Lin A, Cotman CW (1991a) A metabotropic glutamate receptor agonist does not mediate neuronal degeneration in cortical culture.Brain Res 561: 338–343.
Koh J-Y, Palmer E, Cotman CW (1991b) Activation of the metabotropic glutamate receptor attenuatesN-methyl-d-aspartate neurotoxicity in cortical cultures.Proc Natl Acad Sci USA 88: 9431–9435.
Land JM, Goulder P, Johnson AW, Hockaday J (1992) Quinolinate and glutaric aciduria type I.Abstracts of the 30th Annual Symposium of SSIEM, P88.
Lee KS, Frank S, Vanderklish P, Arai A, Lynch G (1991) Inhibition of proteolysis protects hippocampal neurons from ischemia.Proc Natl Acad Sci USA 88: 7233–7237.
Ludolph AC, Hugeon J, Dwivedi MP, Schaumburg HH, Spencer PS (1987) Studies on the etiology and pathogenesis of motor neuron diseases. Lathyrism. Clinical findings in established cases.Brain 110: 149–165.
Ludolph AC, Ullrich K, Bick U, Fahrendorf G, Przyrembel H (1991a) Functional and morphological deficits in late-treated patients with homocystinuria: a clinical, electrophysiological, and MRI study.Acta Neurol Scand 83: 161–165.
Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991b) 3-Nitropropionic acid — exogenous animal neurotoxin and possible human striatal toxin.Can J Neurol Sci 18: 492–498.
Ludolph AC, Seelig M, Ludolph AG, Sabri MI, Spencer PS (1992) Cellular energy deficits and excitotoxic lesions induced by 3-nitropropionic acid in vitro.Neurodegeneration 1: 155–161.
Manev H, Favaron M, Siman R, Guidotti A, Costa E (1991) Glutamate neurotoxicity is independent of calpain I inhibition in primary cultures of cerebellar granule cells.J Neurochem 57: 1288–1295.
Matalon R, Naidu S, Hughes JR, Michals K (1983) Non-ketotic hyperglycinemia: Treatment with diazepam — a competitor for glycine receptors.Pediatrics 71: 581–584.
McDonald JW, Johnston MV (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development.Brain Res Rev 15: 41–70.
Meldrum B, Garthwaite J (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease.TIPS 11: 379–387.
Mosinger JL, Price MT, Bai HY, Xiao H, Wozniak DF, Olney JW (1991) Blockade of both NMDA and non-NMDA receptors is required for optimal protection against ischemic neuronal degeneration in the in vivo adult mammalian retina.Exp Neurol 113: 10–17.
Nozaki K, Beal MF (1992) Neuroprotective effects ofl-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats.J Cereb Blood Flow Metab 12: 400–407.
Ohta Y, Ochi N, Mizutani N, Hayakawa C, Watanabe K (1990) Non-ketotic hyperglycinemia: Therapeutic attempt with NMDA receptor antagonist.Abstracts of the 5th International Congress on Inherited Metabolic Diseases, P79.
Olney JW (1980) Excitotoxic mechanisms of neurotoxicity. In Spencer PS, Schaumburg HH, eds.Clinical and Experimental Neurotoxicology. Baltimore: Williams and Wilkins, 272–294.
Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs.Science 244: 1360–1362.
Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (1991) NMDA antagonist neurotoxicity: Mechanism and prevention.Science 254: 1515–1518.
Riepe M, Hori N, Ludolph AC, Carpenter DO, Spencer PS (1992) Inhibition of energy metabolism by 3-nitropropionic acid activates ATP-sensitive potassium channels.Brain Res 586: 61–66.
Rothman SM (1992) Excitotoxins: Possible mechanisms of action.Ann NY Acad Sci 648: 132–139.
Schmitt B, Steinmann B, Gitzelmann R, Thun-Hohenstein L, Dumermuth G (1992) Dextromethorphan, aN-methyl-d-aspartate antagonist, in the treatment of non-ketotic hyperglycinemia.Abstracts of the 30th Annual Symposium of SSIEM, O5.
Schoepp DD, Johnson BG, Salhoff CR, McDonald JW, Johnston MV (1991) In vitro and in vivo pharmacology of trans- and cis-(+)-1-amino-1,3-cyclopentanedicarboxylic acid: Dissociation of metabotropic and ionotropic excitatory amino acid receptor effects.J Neurochem 56: 1789–1796.
Sharp FR, Jasper P, Hall J, Noble L, Sagar SM (1991) MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex.Ann Neurol 30: 801–809.
Stokke O, Goodman SI, Moe PG (1976) Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and β-hydroxyglutarate: Explanation of the symptoms in glutaric aciduria.Clin Chim Acta 66: 411–415.
Teitelbaum JS, Zatorre RJ, Carpenter S et al (1990) Neurological sequelae of domoic acid intoxication due to the ingestion of contaminated mussels.N Engl J Med 322: 1781–1787.
Turski L, Bressler K, Rettig K-J, Löschmann P-A, Wachtel H (1991) Protection of substantia nigra from MPP+ neurotoxicity byN-methyl-d-aspartate antagonists.Nature 349: 414–418.
Watkins JC, Evans RH (1981) Excitatory amino acid neurotransmitters.Annu Rev Pharmacol Toxicol 21: 165–204.
Zeevalk GD, Nicklas WJ (1991) Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition.J Pharmacol Exp Ther 257: 870–878.
Zeevalk GD, Nicklas WJ (1992) Evidence that the loss of the voltage-dependent Mg2+ block at theN-methyl-d-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism.J Neurochem 59: 1211–1220.
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Ludolph, A.C., Riepe, M. & Ullrich, K. Excitotoxicity, energy metabolism and neurodegeneration. J Inherit Metab Dis 16, 716–723 (1993). https://doi.org/10.1007/BF00711903
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DOI: https://doi.org/10.1007/BF00711903