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Transient Inhibition of Glutamate Uptake In Vivo Induces Neurodegeneration when Energy Metabolism Is Impaired
Author(s) -
Del Rayo SánchezCarbente Ma.,
Massieu Lourdes
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720129.x
Subject(s) - glutamate receptor , microdialysis , extracellular , neurodegeneration , excitotoxicity , in vivo , biology , metabolism , glutamic acid , citric acid cycle , chemistry , biochemistry , pharmacology , medicine , amino acid , receptor , microbiology and biotechnology , disease
: Impairment of glutamate transport during ischemia mightbe related to the elevation of the extracellular concentration of glutamateand ischemic neuronal damage. Additionally, impairment of energy metabolism invivo leads to neurodegeneration apparently mediated by a secondary excitotoxicmechanism. In vitro observations show that glucose deprivation and inhibitionof energy metabolism exacerbate the toxic effects of glutamate. We havepreviously shown that glutamate uptake inhibition in vivo by l ‐ trans ‐pyrrolidine‐2,4‐dicarboxylate (PDC) leads to a substantial elevation in the extracellular concentration of excitatory amino acids that is not associated with cell death. These observations suggest that energy depletion during ischemia might be determinant of ischemic neuronal damage. To investigate whether impairment of energy metabolism in vivo increases neuronal susceptibility to glutamate uptake inhibition, we studied the effect of glutamate accumulation induced by the intrahippocampal or intrastriatal administration of PDC in energy‐deficient rats chronically treated with 3‐nitropropionic acid (3‐NP), which irreversibly inhibits the tricarboxylic acid cycle and electron transport chain. Extracellular glutamate levels were monitored by HPLC from fractions collected from microdialysis probes, and neuronal damage was evaluated by histological analysis. Our results show that glutamate uptake inhibition leads to marked neuronal damage in energy‐deficient rats but not in intact animals, which apparently is not related to an additional elevation of glutamate levels induced by 3‐NP.