Shc C蛋白参与罗哌卡因脊髓神经毒性机制的作用

The severe neural complications of spinal anesthesia mainly attribute to the neurotoxicity of local anesthetics, but unfortunately the specific mechanism is still unknown. Previous studies showed that MAPK, Akt,oxidative stress and apoptosis involoved in the neurotoxicity of ropivacaine. However the upstream or the regulation of these pathways are still not very clear. Shc C (N-shc),the phosphotyrosine-binding domain-containing adaptor proteins that signal to cellular differentiation and apoptosis pathway,involoved MAPK, Akt,oxidative stress and so on. The more important thing is that Shc C protein have dual regulation mechanism,it can not only regulate neural survive but also apoptosis.Whether the Shc C protein involved in ropivacaine's neurotoxicity is still unknown, so we employed the RNA interference technique to knock down gene expression of Shc C in neuronal cell to study the effect of Shc C on the neurotoxicity of ropivacaine in vivo and vitro. We suggest that specific Shc C inhibition may have potential therapeutic value, and that Shc C is a novel target for gene therapy of local anesthetics's neurotoxicity.

局麻药物的神经毒性是椎管内麻醉后出现神经并发症的重要原因，然而具体机制不清。既往实验发现MAPK、Akt以及细胞凋亡参与了罗哌卡因脊髓神经毒性，然而其上游通路以及调控因素尚不明确。Shc C蛋白也称为N-shc蛋白，是一种重要的酪氨酸信号适配蛋白，可在中枢神经系统传递和活化很多重要信号，如调节MAPK和Akt的活化以及氧化应激、细胞凋亡等多种重要的细胞活动；且Shc C蛋白调控信号通路具有双重调节机制，不仅可对神经细胞产生保护作用还可产生损伤性的病理作用，故Shc C蛋白在神经系统的信号传递中处于核心的调控作用，而其是否参与了罗哌卡因脊髓神经毒性目前尚不清楚，故本项目拟采用RNA干扰的技术下调Shc C蛋白的表达，通过在体和离体的实验来检测MAPK通路中P38/JUN/ERK以及AKT的表达变化来初步揭示Shc C蛋白对罗哌卡因神经毒性机制的调控，为防治局麻药物的神经毒性进一步提供依据。