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: 6296737
• 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/6296737
• 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.

NMDA毒性的神经保护作用α-二氟甲基氨酸的毒性 和尼古丁N-甲基-D-天冬氨酸（NMDA）神经毒性是一种模型 反映人类疾病关键方面的中风。 NMDA 激活谷氨酸受体的亚型 钙。 钙原因的涌入以及其他影响 鸟氨酸脱羧酶（ODC）的激活，第一个和速率 - 限制多胺合成的酶。 假定是 精子（NMDA受体）生物合成增加的结果 进一步激活，更多的钙进入细胞质，导致 致命的恶性循环。 不可逆的ODC抑制剂α- 差异甲基氨酸（DFMO）防止NMDA神经毒性， 据说是因为它降低了精子水平。 但是，多胺 - DFMO的耗尽活性很低，由于法规复杂， 它实际上增加了脑皮质中的精子浓度。 DFMO神经保护活性的另一种解释是 在这里提议。 DFMO是海马切片中一种温和的兴奋剂，因为 是另一种神经保护剂尼古丁。 这个温和的 特定刺激增加了神经营养蛋白的合成， 促进神经元生存。 海马切片和皮质细胞 培养物将用于测试上述模型的预测， 其中一些是：DFMO在存在的情况下是神经保护 非刺激剂的外源腐败，ODC抑制剂不会 保持神经保护性，DFMO和尼古丁都会增加 神经营养蛋白，DFMO和尼古丁都不是神经保护 存在针对神经营养蛋白的抗体。 这项工作将有助于阐明ODC和多胺的作用 在神经毒性和文本中的假设 DFMO和DFMO等不同化合物的神经保护作用 尼古丁。