NEUROPROTECTION FROM NMDA TOXICITY BY ALPHA DIFLUOROMETHYLORNITHINE AND NICOTINE

α 二氟甲基鸟氨酸和尼古丁对 NMDA 毒性的神经保护作用

• 批准号: 6107692
• 负责人: P. A. Ferchmin
• 金额: $ 13.96万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107692
• 关键词: GABA receptor; NMDA receptors; brain cell; bungarotoxins; difluoromethylornithine; disease /disorder model; electrophysiology; enzyme activity; enzyme inhibitors; enzyme linked immunosorbent assay; hippocampus; laboratory rat; neuroprotectants; neurotoxicology; neurotrophic factors; nicotine; ornithine decarboxylase; physical chemical interaction; polyamines; putrescine; spermidine; stroke; tissue /cell culture

Neuroprotection from NMDA toxicity by alpha-difluromethylornithine and nicotine N-methyl-D-aspartate (NMDA) neurotoxicity is a model of stroke that reflects critical aspects of the human disease. NMDA activates a subtype of glutamate receptors that is permeant to calcium. The influx of calcium causes, among other effects, activation of ornithine decarboxylase (ODC), the first and rate- limiting enzyme of polyamine synthesis. It is assumed that as a result of the increased biosynthesis of spermine, the NMDA receptor is further activated and more calcium enter the cytoplasm leading to a deadly vicious cycle. The irreversible ODC inhibitor alpha- difluoromethylornithine (DFMO) prevents NMDA neurotoxicity, supposedly because it lowers spermine level. However, the polyamine- depleting activity of DFMO is low and because of complex regulations, it actually increases spermine concentration in cerebral cortex. An alternative explanation for DFMO neuroprotective activity is proposed here. DFMO is a mild stimulant in the hippocampal slice, as is another neuroprotective agent, nicotine. This moderate and specific stimulation increases the synthesis of neurotrophins, which promote neuronal survival. Hippocampal slices and cortical cell cultures will be used to test the predictions of the above model, some of which are: DFMO is neuroprotective in the presence of exogenous putrescine, ODC inhibitors that are not stimulant will not be neuroprotective, both DFMO and nicotine increase the level of neurotrophins, neither DFMO nor nicotine are neuroprotective in the presence of antibodies against neuroptrophins. This work will contribute to clarify the role of ODC and polyamines in neurotoxicity and text a hypothesis that integrates neuroprotective effects of dissimilar compounds like DFMO and nicotine.

α -二氟甲基鸟氨酸对NMDA毒性的神经保护作用