硫化氢在脑缺血中的双重效应及其机制研究

以往研究表明，脑缺血12h内硫化氢水平升高，与预后呈负相关，外源性硫化氢加重脑损害。最近研究发现，脑缺血后硫化氢水平降低，低剂量的外源性硫化氢减轻脑损伤。本研究组预实验发现：外源性硫化氢的作用与脑缺血不同病理阶段硫化氢水平变化有关，且不同水平的硫化氢通过激活N-甲基-D-天冬氨酸（NMDA）2型受体的不同亚单位（NR2A\NR2B）而产生不同作用。故认为硫化氢具有双重效应，低剂量外源性硫化氢在脑缺血后36h提高硫化氢水平，激活NR2A，产生保护作用，而高剂量外源性硫化氢使其持续高于生理水平，激活NR2B，加重脑损伤。因此，本项目首先通过临床研究分析脑缺血不同病理阶段硫化氢水平与预后的相关性，然后通过动物实验进一步研究不同水平硫化氢的双重效应，并借助电生理和分子生物学技术，研究不同水平硫化氢产生双重效应的分子机制。本项目将深化对硫化氢在脑缺血中作用的理解，并为后续新药设计与开发提供新思路。

It was reported that the plasma level of hydrogen sulfide in 12 hours of stroke onset predispose to poor outcome in clinical stroke and administration of sodium hydrosulfide(NaHS,an H2S donor)significantly increased the infarct volume after middle cerebral artery occlusion(MCAO). However, recent research found that the level of H2S during non-acute phase of stroke is lower than physiological level and a low dose exogenous H2S can protect MCAO rats.Our preliminary resarch also found that a low dose exogenous H2S can decreased the infarct volume 72 hours after the onset of stroke,which was abolished by NR2A-containing NMDA receptor antagonist while a high dose exogenous H2S can enhance the damage of stroke,which was blocked by NR2B-containing NMDA receptor antagonist. Thus, we hypothize that a low dose exogenous can recover the H2S when it is significantly decreased by stroke to activate NR2A, which subsequently promote neurogenesis. However, a high dose exogenous H2S can make it higher than physiological level, which activate NR2B and then promote apoptosis. This program will further identify the opposite treatment in respective pathelogical phase. And then,we will clarify that the physiological level H2S activate NR2A receptor predominantly and enhance the neurogenesis,but a level higher than physiological level activate NR2B predominantly,which enhance the injury. The correlation between the plasma H2S during non-acute phase of stroke and the clinical outcome will also be studied. If this program is approved,we can take the advantage of teaching hospital to combine basci medcine with clinical medcine to deepen the comprehension of the role of H2S in ischemic stroke and promote the invention of new drugs to treat ischemic stroke