In vivo potentiation of glutamate-mediated neuronal damage after chronic administration of the glycolysis inhibitor iodoacetate

L. Massieu, N. Gómez-Román, T. Montiel

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Neuronal damage associated with cerebral ischemia and hypoglycemia might be the consequence of the extracellular accumulation of excitatory amino acids. In previous studies we showed that elevation of glutamate and aspartate extracellular levels by inhibition of its uptake in vivo is not sufficient to induce neuronal damage unless mitochondrial energy metabolism is compromised. In the present study we show that chronic systemic administration of the glycolysis inhibitor iodoacetate (25 mg/kg) induces no damage to the brain per se but enhances neuronal vulnerability to glutamate-mediated neurotoxicity in the hippocampus. Tissue injury is well protected either by antagonizing NMDA glutamate receptors with MK-801 or by administration of pyruvate, a substrate of the tricarboxylic acid cycle. In contrast to systemic treatment, local infusions through a dialysis probe of 5 mM iodoacetate into the hippocampus induced acute lesions not sensitive to MK-801. Iodoacetate intrahippocampal perfusion induced substantial increases in the extracellular levels of glutamate (3.5-fold), taurine (8.8-fold), and particularly aspartate (35-fold). Neuronal damage under this conditions occurs very rapidly as revealed by the histological analysis of animals transcardially perfused immediately after iodoacetate perfusion. Aspartate might contribute to neuronal damage since intrahippocampal administration of this amino acid (600 nmol/μl) induces extensive lesions. The present study might suggest that impairment of glucose oxidation through the glycolytic pathway in vivo facilitates glutamate neurotoxicity. Additionally, the results indicate that pyruvate might prevent as efficiently as glutamate receptor antagonists glutamate-mediated neuronal damage associated with ischemia/hypoglycemia.

Original languageEnglish
Pages (from-to)257-267
Number of pages11
JournalExperimental Neurology
Volume165
Issue number2
DOIs
Publication statusPublished - 31 Oct 2000

Keywords

  • excitotoxicity
  • glutamate transport
  • glycolysis inhibition
  • iodoacetate
  • pyruvate

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