3-Nitropropionic acid is an indirect excitotoxin to cultured cerebellar granule neurons

The ability of N-methyl-D-aspartate (NMDA) receptor agonists and antagonists to modify 3-nitropropionic acid toxicity was studied in cultured rat cerebellar granule neurons. Exposure of these neurons to 3-nitropropionic acid resulted in a concentration and time-dependent neurotoxicity. In contrast to glutamate toxicity, 3-nitropropionic acid toxicity was potentiated by preexposure to subtoxic concentrations of NMDA. Presumably, the 3-nitropropionic acid-induced energy depletion relieved the voltage-dependent Mg2+ block of the NMDA receptor and induced vulnerability to subtoxic concentrations of NMDA receptor agonists. MK-801 and 2-amino-5-phosphonovaleric acid (APV) delayed but did not prevent 3-nitropropionic acid toxicity, indicating that prolonged exposure to 3-nitropropionic acid ultimately resulted in histotoxic neuronal death. We conclude that there are at least two distinct mechanisms of 3-nitropropionic acid toxicity of cerebellar granule neurons, one indirectly involving NMDA receptor-mediated excitotoxicity and one that is NMDA receptor-independent.