Does spreading depolarization facilitate neurnal injury when cerebral tissue is metabolically compromised by the vasoconstrictor endothelin-1?

当脑组织受到血管收缩剂内皮素-1 的代谢损害时，扩散去极化是否会促进神经损伤？

• 批准号: 208559819
• 负责人: Professor Dr. Jens P. Dreier
• 金额: --
• 依托单位: Centrum für Schlaganfallforschung Berlin (CSB)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/208559819?language=en
• 关键词: Does; spreading; depolarization; facilitate; neurnal

All neurons depolarize in the absence of oxygen, but it seems that those that are more resistant to hypoxic/ischemic injury do so gradually. The term spreading depolarization describes the spectrum of abrupt depolarizations, and accumulating evidence suggests that they facilitate neuronal death. Here, we would like to investigate this hypothesis using the rat brain topical endothelin-1 (ET-1) model which allows titrating the constrictive effect of ET-1 on the vasculature. Thus, tissue can be poised close to the threshold where ischemic-metabolic compromise becomes detrimental. Spreading depolarization seems to indicate that this threshold is crossed since we found in neocortex that exposure to ET-1 only caused neuronal death when animals displayed spreading depolarization. Here, we aim to study the ET-1 effect on cerebellum and brainstem which only generate spreading depolarization in presence of conditioning media increasing neuronal excitability. Will conditioning media allow ET-1 to induce spreading depolarization associated with neuronal injury? In neocortex, we aim to investigate, using different ET-1 concentrations, whether faster recovery within the depolarization continuum shifts the cell death from necrosis toward apoptosis. It will also be studied whether two multidrug cocktails inhibiting persistent dendritic inward currents are sufficient to prevent spreading depolarization and neuronal injury when vessels are markedly constricted by ET-1 combined with NO synthase inhibition.

所有的神经元在缺氧的情况下都会退化，但似乎那些对缺氧/缺血损伤更有抵抗力的神经元会逐渐退化。术语扩展去极化描述了突然去极化的频谱，并且越来越多的证据表明它们促进神经元死亡。在这里，我们想研究这一假设，使用大鼠脑局部内皮素-1（ET-1）模型，它允许滴定ET-1对血管系统的收缩作用。因此，组织可以接近缺血-代谢损害变得有害的阈值。扩散性去极化似乎表明这个阈值被跨越，因为我们发现在新皮层中，当动物显示扩散性去极化时，暴露于ET-1仅引起神经元死亡。在这里，我们的目的是研究ET-1对小脑和脑干的影响，只有在条件培养基增加神经元兴奋性的存在下才产生扩散性去极化。条件培养基是否允许ET-1诱导与神经元损伤相关的扩散性去极化？在新皮层，我们的目的是调查，使用不同的ET-1浓度，是否更快的恢复内的去极化连续转移的细胞死亡从坏死到凋亡。还将研究两种多药鸡尾酒抑制持续的树突状细胞内向电流是否足以防止扩散去极化和神经元损伤时，血管显着收缩ET-1结合NO合酶抑制。