七氟醚影响大鼠脑发育过程中MAPK和Akt/GSK3β/CRMP2信号通路
祝贺贵州医科大学麻醉学院15级专业学位研究生文春雷顺利毕业
研究方向：麻醉与心脏电生理 指导老师：高鸿教授
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Influence of sevoflurane exposure on mitogen.activated protein kinases and Akt/GSK.3β/CRMP.2 signaling pathways in the developing rat brain
背景与目的
长时间暴露在吸入麻醉下，可引起大鼠脑发育过程中脑神经退行性病变，其具体机制不明。当前的研究仅观察到与MAPK和Akt/GSK3β/CRMP2信号通路相关的蛋白在大脑皮质中的表达。
方 法
将7日龄（P7）新生C57BL / 6小鼠随机分成2组，并将其暴露于2.6％七氟醚或空气中6小时。使用末端脱氧核糖核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色以及活化的天胱蛋白酶-3和α-荷瘤蛋白的表达来检测小鼠大脑皮质中的神经元细胞凋亡。通过检测细胞间的P-ERK1/2、CREB、p-p38、NF-κB、p-JNK来观察MAPK信号通路。通过检测p-Akt, p-GSK-3β 和 p-CRMP-2的表达来评价Akt/GSK-3β/CRMP-2信号通路。
结 果
七氟醚显著增加大脑后皮层、额叶皮质、顶叶联合皮层的细胞凋亡。增加细胞凋亡酶-3，促进α-胞影蛋白形成145kDa和120kDa的片段。七氟醚抑制ERK1/2 和 CREB的磷酸化，刺激p38 和 NF-κB的磷酸化，不显著影响JNK的磷酸化。更重要的是，七氟醚抑制Akt的磷酸化，减少GSK-3β的ser9位点、增加CRMP2的Thr514位点的磷酸化水平。
结 论
这些结果提示多信号通路包括ERK1/2, P38 和 Akt/GSK-3β/CRMP-2与七氟醚诱发大鼠脑发育过程中神经细胞凋亡有关。MAPK信号通路与细胞生长和病理状态，包括神经系统发育和神经变性。Akt/GSK-3β/CRMP-2信号通路与细胞增殖，分化，变形性和凋亡。
原始文献摘要
Liu Y, Liu C, Zeng M, et al. Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3β/CRMP-2 signaling pathways in the developing rat brain[J]. Experimental & Therapeutic Medicine, 2018:2066-2073.
Abstract. Prolonged exposure to volatile anesthetics causes neurodegeneration in developing animal brains. However, their underlying mechanisms of action remain unclear. The current study investigated the expression of proteins associated with the mitogen-activated protein kinases (MAPK) and protein kinaseB (Akt)/glycogen synthase kinase-3β(GSK-3β)/collapsing response mediator protein 2 (CRMP-2) signaling pathways in the cortices of neonatal mice following exposure to sevoflurane. Seven-day-old (P7) neonatal C57BL/6 mice were randomly divided into 2 groups and either exposed to 2.6% sevoflurane or air for 6 h. Terminal deoxyribonucleotide transferase mediated dUTP nick end labeling (TUNEL) staining, as well as the expression of activated caspase-3 and α-fodrin, was used to detect neuronal apoptosis in the cortices of mice. MAPK signaling pathways were investigated by detecting the expression of phosphorylated (p-) extracellular signal-regulated kinase 1/2 (ERK1/2), p-cyclic adenosine monophosphate response element-binding protein (CREB), p-p38, p-nuclear factor (NF-κB) and p-c-Jun N-terminal kinase (p-JNK). Akt/GSK-3β/CRMP-2 signaling pathways were assessed by detecting the expression of p-Akt, p-GSK-3β and p-CRMP-2 in the cortices of P7 mice 2 h following exposure to sevoflurane. The results demonstrated that sevoflurane significantly increased the apoptosis of cells in the retrosplenial cortex (RS), frontal cortex (FC) and parietal association cortex (PtA), increased the expression of cleaved caspase-3 expression and promoted the formation of 145 kDa and 120 kDa fragments from αfodrin. Sevoflurane inhibited the phosphorylation of ERK1/2 and CREB, stimulated the phosphorylation of p38 and NF-κB, but did not signifcantly affect the phosphorylation of JNK. Furthermore, sevoflurane inhibited the phosphorylation of Akt, decreased the phosphorylation of GSK-3β at ser9 and increased the phosphorylation of CRMP2 at Thr514. These results suggest that multiple signaling pathways, including ERK1/2, P38 and Akt/GSK-3β/CRMP-2 may be involved in sevoflurane induced neuroapoptosis in the developing brain.
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