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.
Weller
M
M
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, MD 20892.
Paul
S M
SM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D003594:Cytoplasmic Granules / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004594:Electrophysiology; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects
D005971:Glutamates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C015392:3-nitropropionic acid