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 administered in 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 mM after 20 h of incubation in 20.0 mM glucose medium. Despite its selective toxicity in 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.
Fink
S L
SL
Department of Neuroscience, Stanford University, California 94305, USA.
Ho
D Y
DY
Sapolsky
R M
RM
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D018698:Glutamic Acid; C015392:3-nitropropionic acid