Energy and Glutamate Dependency of 3-Nitropropionic Acid Neurotoxicity in Culture

3-Nitropropionic acid (3-NP) irreversibly inhibits the activity of the mitochondrial enzyme succinate dehydrogenase, leading to selective striatal lesions when administeredin vivo.We studied the effects of 3-NP on dissociated cultures of neurons and glia with the following findings: (a) 3-NP killed...

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Bibliographic Details
Published in:Experimental neurology 1996-04, Vol.138 (2), p.298-304
Main Authors: Fink, Sheri L., Ho, Dora Y., Sapolsky, Robert M.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Brain - cytology
Brain - drug effects
Cells, Cultured
Corpus Striatum - cytology
Corpus Striatum - drug effects
Dose-Response Relationship, Drug
Energy Metabolism
Excitatory Amino Acid Antagonists - pharmacology
Food toxicology
Glutamic Acid - pharmacology
Medical sciences
Neurotoxins - metabolism
Nitro Compounds
Propionates - pharmacology
Rats
Rats, Sprague-Dawley
Substrate Specificity
Toxicology
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Summary:3-Nitropropionic acid (3-NP) irreversibly inhibits the activity of the mitochondrial enzyme succinate dehydrogenase, leading to selective striatal lesions when administeredin vivo.We studied the effects of 3-NP on dissociated cultures of neurons and glia with the following findings: (a) 3-NP killed cultured striatal neurons with a median lethal dose of 2.5 mMafter 20 h of incubation in 20.0 mMglucose medium. Despite its selective toxicityin vivo,cultured striatal, hippocampal, septal, and hypothalamic neurons were similarly sensitive to 3-NP incubation. (b) 3-NP's effects were remarkably energy substrate dependent, with the median lethal dose dropping over an order of magnitude when glucose concentrations were lowered to 3.0 mM, a condition that was itself nontoxic. Cultures exposed to 3-NP had a far greater sensitivity to energy availability than those exposed to glutamate. (c) Recent work suggests that 3-NP toxicity may be partially mediated by excitotoxins. Our experiments show that neither kynurenic acid, a nonspecific glutamate receptor antagonist, nor the NMDA-receptor antagonist,dl-2-amino-7-phosphonoheptanoic acid, either in combination or alone, reduced 3-NP toxicity in striatal cultures. However, the noncompetitive NMDA antagonist MK-801 did attenuate 3-NP toxicity.
ISSN:0014-4886
1090-2430
DOI:10.1006/exnr.1996.0068