孕期应用吸入麻醉药对胎鼠及出生后幼鼠的神经毒性作用研究

Anesthesia neurotoxicity in the developing brain has been investigated in animals and in humans. Our previous study showed sevoflurane anesthesia in pregnant mice increased IL-6 levels and reduced PSD-95 in fetal and reduced synaptophysin levels in offspring mice, lead to learning and memory impairment in P31 offspring mice. Moreover, IL-6 antibody can mitigate the sevoflurane-induced reduction in PSD-95 levels in the neurons. Based on these studies, we speculate that inhalation anesthesia in pregnancy induced inflammatory cytokines increase in fetal brain, lead to mitochondrial dysfunction, result in synaptic loss and learning and memory dysfunction in offspring mice eventually. To verify this hypothesis, we will do the experiments in whole animals, brain slices and cell culture with neurophysiological technology, immunoblotting, flow cytometry, immune staining and behavioral testing in vitro and in vivo, to find the possible mechanisms of neuroinflammation caused by inhalation anesthetics mediated synaptic loss, clarify the key role of mitochondrial dysfunction in inhalation anesthetics induced neurotoxicity in developing brain. The aim is to provide theoretical basis for the prevention and treatment of anesthesia induced developing brain impairment.

麻醉对发育期大脑的神经毒性在动物实验和临床研究已有报导。我们的前期实验发现，孕期应用七氟烷麻醉可引起胎鼠脑组织IL-6升高及PSD-95降低，导致出生后31天幼鼠海马区突触减少和学习记忆功能障碍，离体细胞实验显示IL-6抗体可以减轻麻醉药造成的PSD-95降低程度。基于这些研究，我们推测，孕期应用吸入麻醉药导致的胎儿脑组织炎症因子增加可引起神经细胞线粒体功能异常，从而导致神经突触减少，最终造成出生后幼鼠学习记忆功能减退。为验证此假说，在本项目中我们将在离体和在体两个系统，整体动物、脑片和细胞三个水平，采用细胞培养、神经电生理、免疫印迹、流式细胞术、免疫组化以及行为学检测等手段，以炎症因子、线粒体与突触的关系为核心，深入研究吸入麻醉药介导的神经免疫炎症导致突触减少的可能机制，阐明线粒体功能异常在吸入麻醉药对发育期大脑神经毒性中的关键作用，为预防和治疗麻醉导致的发育期大脑神经损伤提供理论基础。