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 st riatal lesions when administered in vivo. We studied the effects of 3- NP on dissociated cultures of neurons and glia with the following find ings: (a) 3-NP killed cultured striatal neurons with a median lethal d ose of 2.5 mM after 20 h of incubation in 20.0 mM glucose medium. Desp ite its selective toxicity in vivo cultured striatal, hippocampal, sep tal, and hypothalamic neurons were similarly sensitive to 3-NP incubat ion, (b) 3-NP's effects were remarkably energy substrate dependent, wi th the median lethal dose dropping over an order of magnitude when glu cose concentrations were lowered to 3.0 mM, a condition that was itsel f nontoxic. Cultures exposed to 3-NP had a far greater sensitivity to energy availability than those exposed to glutamate. (c) Recent work s uggests that 3-NP toxicity may be partially mediated by excitotoxins. Our experiments show that neither kynurenic acid, a nonspecific glutam ate receptor antagonist, nor the NMDA-receptor antagonist, DL-2-amino- 7-phosphonoheptanoic acid, either in combination or alone, reduced 3-N P toxicity in striatal cultures. However, the noncompetitive NMDA anta gonist MK801 did attenuate 3-NP toxicity. (C) 1996 Academic Press, Inc .