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

所有的神经元在没有氧气的情况下都会去极化，但那些对缺氧/缺血损伤更具抵抗力的神经元似乎会逐渐去极化。术语扩展去极化描述了突然去极化的频谱，越来越多的证据表明它们促进了神经元的死亡。在这里，我们想要使用大鼠脑局部内皮素-1(ET-1)模型来研究这一假说，该模型允许滴定ET-1对血管系统的收缩效应。因此，组织可以稳定在接近缺血-代谢妥协变得有害的阈值。扩散性去极化似乎表明这一阈值被越过，因为我们在新皮质中发现，只有当动物表现出扩散性去极化时，暴露于ET-1才会导致神经元死亡。在此，我们旨在研究ET-1对小脑和脑干的影响，这些脑干在条件性介质增加神经元兴奋性的情况下只产生扩张性去极化。条件性介质会允许ET-1诱导与神经元损伤相关的扩散性去极化吗？在新皮质，我们的目标是研究，使用不同的ET-1浓度，去极化连续体内更快的恢复是否将细胞死亡从坏死转变为凋亡。还将研究两种抑制持续树突状内向电流的多药鸡尾酒是否足以防止扩张的去极化和当ET-1联合NO合酶抑制明显收缩血管时神经元损伤。

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.