3-Nitropropionic acid: an astrocyte-sparing neurotoxin in vitro

3-Nitropropionic acid (NPA), an inhibitor of succinate dehydrogenase, is di etary neurotoxin. It is not known if neurons and astrocytes differ in their vulnerability to NPA, therefore, we investigated its toxicity in primary c ultures of cerebellar granule cells and astrocytes. NPA inhibited succinate dehydrogenase and tricarboxylic acid cycle activity to the same degree in neurons and astrocytes. Even so NPA acid was 16 times more toxic to neurons than to astrocytes (LC50: 0.7 and 11 mM, respectively). The neurotoxicity of NPA was mediated by NMDA-receptor activation, calcium influx, and format ion of reactive oxygen species, as revealed by the protective effect of NMD A-receptor blockade, the accumulation of Ca-45, and the protective effect o f N-t-butyl-alpha-phenylnitron (PBN), a scavenger of reactive oxygen specie s. Cytotoxic concentrations of NPA caused a reduction in the intracellular level of glutathione, which probably contributed to the oxidative damage in both neurons and astrocytes. The relative resistance of astrocytes to NPA appeared to be related to their low tricarboxylic acid cycle activity (5%-1 0% of that in neurons) and to the inability of NPA to cause astrocytic calc ium overload. We conclude that NPA acid predominantly is an astrocyte-spari ng neurotoxin. (C) 1999 Elsevier Science B.V. All rights reserved.