围心脏停搏期的远程缺血处理诱导大鼠内源性脑保护的实验研究

Cerebral injury is one of the main performance of post cardiac arrest syndrome, and it is also the main cause of death of those patients who got a return of spontaneous circulation. Cardiopulmonary resuscitation promoted neuron ischemia/reperfusion injury, and the subsequent opening of cerebral cellular mitochondrial permeability transition pore(mPTP) is a main part of the mechanism of neuron apoptosis. Researches reported in recent years had verified that remote preconditioning or post-conditioning performed by transient limb ischemia aimed to an important organ could introduce an endogenous organic protection.We first reported in China that rats' limb ischemia during cardiac ischemia period (remote perconditioning) could introduce myocardial protection and decrease the expression of pro-apoptosis protein. The mechanism was related with inhibition the opening of mPTP. This subject, based upon our preliminary works, proposed a new cerebral protection strategy which should be performed by remote preconditioning, perconditioning or post-conditioning peri-cardiac arrest period. This strategy would promote brain protection by inhibition of the opening of mPTP and decreasing cellular apoptosis. The study is planned to use a choking rat's CA/CPR model to investigate the relationship between transient limb ischemia and cerebral protecion, the mechanism of anti-apoptosis. The ultimate aim is to seek a applicative cerebal protection stratege for those CA patients.

心肺复苏后脑损伤是心脏停搏（CA）患者复苏后综合症的主要表现之一，也是自主循环恢复后致死的主要原因。心肺复苏造成脑神经细胞的缺血再灌注损伤，继而导致线粒体通透性转换孔（mPTP）的开放是造成脑神经凋亡及脑损伤的主要机制。近年研究发现针对目标脏器进行的短暂肢体缺血预处理和后处理能诱导内源性脏器保护。我们在国内首先发现大鼠心肌缺血期肢体缺血处理也可诱导心肌保护，减少促凋亡蛋白表达，其作用机制与抑制心肌线粒体通透性转换孔(mPTP)的开放有关。本研究在我们前期工作基础上，提出利用围心脏停搏期的远程缺血处理，进行策略性的内源性脑保护的诱导，以达到抑制mPTP开放，减轻脑细胞凋亡，从而促进脑保护，减轻脑损伤。本研究拟采用窒息性大鼠CA/CPR模型，探讨围CA期肢体缺血处理与脑保护的关系，抗凋亡机制，并探求较适用的内源性脑保护策略。

该项目计划对围心跳骤停期肢体缺血和脑损伤的关系开展研究，在获得国家自然科学基金资助后，该项目进展顺利，总共发表3篇论文，圆满完成了预期的目标。通过窒息法建立大鼠心跳骤停模型，比较围心跳骤停期不同时间的远程缺血处理和大鼠脑损伤的关系，研究表明远程缺血前处理、远程缺血后处理可改善大鼠心肺复苏后NDS评分，但远程缺血中处理未发挥出显著的神经功能保护作用。我们进一步对其机制进行研究，发现远程缺血前处理、远程缺血后处理对心肺复苏大鼠的神经功能保护机制与抑制海马神经元细胞线粒体通透性转换孔（mPTP）开放，减少海马神经元细胞凋亡相关，同时我们还使用了mPTP阻断剂环孢霉素A（CsA），CsA可直接阻止mPTP的开放,减少脑神经元细胞凋亡，而远程缺血后处理抑制mPTP开放程度较CsA弱，但是神经保护效果却相当，这一结果也提示抑制海马区神经元细胞mPTP开放是缺血后处理发挥其神经功能保护作用的机制之一，但不是唯一的机制。