Weller M, Paul S M
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, MD 20892.
Eur J Pharmacol. 1993 Oct 1;248(3):223-8. doi: 10.1016/0926-6917(93)90048-u.
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.
在培养的大鼠小脑颗粒神经元中研究了N-甲基-D-天冬氨酸（NMDA）受体激动剂和拮抗剂改变3-硝基丙酸毒性的能力。将这些神经元暴露于3-硝基丙酸会导致浓度和时间依赖性神经毒性。与谷氨酸毒性相反，预先暴露于亚毒性浓度的NMDA可增强3-硝基丙酸毒性。据推测，3-硝基丙酸诱导的能量耗竭解除了NMDA受体的电压依赖性Mg2+阻断，并诱导了对亚毒性浓度NMDA受体激动剂的易感性。MK-801和2-氨基-5-磷酸戊酸（APV）可延迟但不能阻止3-硝基丙酸毒性，表明长时间暴露于3-硝基丙酸最终导致组织毒性神经元死亡。我们得出结论，小脑颗粒神经元的3-硝基丙酸毒性至少有两种不同机制，一种间接涉及NMDA受体介导的兴奋性毒性，另一种与NMDA受体无关。
