全麻药丙泊酚对兴奋性神经递质传递通路的影响及其分子机制

Propofol is the most widely used general anaesthetic in surgery, ICU and outpatient service all over the world nowadays. But, it exerts severe inhibitory effects on cardiovascular system. The reason is thought that the sympathetic nerve system is inhibited. However, the molecular mechanism is unknown. We investigate this inhibition through the secretary cells of catecholamine but not the target organs by borrowing the research idea from exocytosis study. Moreover, this indicates that propofol is probably involved in the excitatory neurotransmitter release pathway since catecholamine belongs to excitatory neurotransmitter. Therefore, general anaesthesia perhaps inhibits excitatory synaptic transmission, which is not really identified, via a presynaptic mechanisms as well as enhance the synaptic inhibition through GABA A receptor. We explore the inhibitory effect on excitatory synaptic neurotransmission pathway and the important proteins of the pathway to elucidate the mechanism of general anaesthesia. Our research helps to understand the molecular mechanism of general anaesthesia not only for the improvement the safety of clinical anaesthesia practice but also for the R&D of new general anaesthetic drugs.

全麻药丙泊酚是目前国内外使用最广泛的短效静脉麻醉药，广泛用于手术，ICU和无痛诊疗等，然而，丙泊酚有严重的循环系统抑制，比较公认的看法是抑制了交感-肾上腺系统，但分子水平上的研究阙如。本研究以交感-肾上腺系统激素分泌细胞为实验模型，测试儿茶酚胺类激素分泌是否减少; 同时, 由于儿茶酚胺属于兴奋性神经递质,与增强抑制性突触传递（GABA A受体介导）相对应，丙泊酚全麻可能同时抑制了兴奋性神经递质传递而发挥"麻醉"作用；丙泊酚对其传递通路本身的抑制是全麻研究的难点之一，其影响机制可能与syntaxin1A等构成兴奋性突触传递通路的重要蛋白有关。全麻原理是麻醉学最重要的基本理论之一, 基于对全麻机制的不了解以及全麻药物本身的高度毒性，全麻本身还承载着极高的风险，阐明全麻原理对提高全身麻醉的安全性有重要意义，对高效安全机制明确的全麻新药的研发具有十分巨大的临床和商业价值。

本项目是一年期项目，课题前半部分是在国内的实验室完成，后半部分是在国外合作者的实验室-加拿大多伦多大学医学院多伦多西区医院（研究所）完成。在国外的课题所有花费由加拿大基金资助（Canadian Institute of Health Science, CIHR). 课题的后期实验中有突破性进展，目前的数据分析表明：全麻药丙泊酚在全麻过程中引起的低血压，与儿茶酚胺类激素释放受到抑制相关，具体机制是：丙泊酚不仅没有抑制突触前外分泌机制,更可能是增强了该机制。实验结果与目前国际上已经发表的美国芝加哥大学的研究结果相反，所以虽然前期已经做出大量包括电子显微镜照片在内的大量数据，但考虑到后期在国外的新发现的重要性，决定就这部分新近做出来的结果先投稿。目前已经投稿到美国麻醉协会的《Anesthesiology》,该杂志是麻醉专业领域里最权威的杂志，影响因子6.168.