脑缺血再灌注损伤是导致神经功能障碍的重要原因,但其有效的治疗措施十分有限。异氟醚是临床上常用吸入麻醉药物,以往研究提示其后处理可对脑缺血再灌注损伤产生神经保护作用,然而其作用机制尚不清楚。本课题组研究发现异氟醚后处理可以通过调节TGF-β1/Smad-MAPKs信号通路减轻大鼠海马区的神经损伤,然而,异氟醚后处理后,TGF-β的转录调控机制尚且未知。研究提示在大鼠脑缺血再灌注损伤后MEF2转录因子有功能表达,且MEF2可调控TGF-β转录水平,因此我们提出假说:异氟醚后处理大鼠脑缺血再灌注损伤时,可通过MEF2上调TGF-β转录水平,通过抑制炎症反应,产生神经保护作用。本课题拟通过建立大鼠模型,采用分子克隆和基因沉默技术、电生理技术、免疫荧光、ChIP等技术,阐述MEF2对TGF-β的转录调控在异氟醚后处理对抗脑缺血再灌注损伤中的作用,为异氟醚后处理诱导的脑保护作用找到新的作用机制。

Cerebral ischemia-reperfusion injury plays a key role in neuronal dysfunction, and effective treatments are still limited. Isoflurane is a common clinic volatile anesthetic. Numerous studies established that isoflurane postconditioning can induce neuroprotective effect. However, mechanism of it remains unclear. Our previous studies demonstrated isoflurane postconditioning could reduce cerebral ischemia-reperfusion injury via modulating the TGF-β1/Smad-MAPKs signaling pathway in rats' hippocampal. Nevertheless, mechanism of transcriptional regulation in TGF-β signaling pathway is still unclear. Most research articles indicate MEF2 is often functionally expressed during process of ischemia-reperfusion in rats' brain. In addition, MEF2 is vital for transcriptional regulation in TGF-β signaling pathway. We assume that neuroprotective function of isoflurane postconditioning in cerebral ischemia-reperfusion is regulated by MEF2 through TGF-β signaling pathway and inflammatory pathway, which will activate the related signaling proteins’ expression by signaling crosstalk. They may be the new mechanisms of isoflurane in the aspect at non-anesthetic effect. To prove this hypothesis, ischemia-reperfusion experimental model will be established in vivo and in vitro of rats brain; measures of molecular biology, immune fluorescence technology and chromatin immunoprecipitation will be taken to observe the regulative effects of MEF2 through TGF-β signaling pathways in isoflurane postconditioning in rats. To testify this new mechanism of isoflurane, technology of etholoy, functional proteomics and cytology will be adopted. We anticipate results of our researches will provide the new theoretical basis for precaution of cerebral ischemia-reperfusion injury.