XingNaoJing Alleviated Adult Mice Cognitive Dysfunction Induced by Sevoflurane through Inhibition of the Notch Signaling Pathway
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摘要:
目的 探究醒脑静注射液减轻七氟烷引起认知障碍的机制及Notch信号通路的相关作用。 方法 将36只8~12周龄的SPF级雄性C57BL/6J小鼠随机分成3组: 对照组、七氟烷组以及七氟烷+醒脑静组，每组12只。Morris水迷宫检测各组小鼠认知行为能力; 免疫荧光及qPCR技术检测各组小鼠的海马炎症水平; 免疫荧光检测各组小鼠海马神经干细胞的增殖功能; Western blot检测Notch信号通路相关蛋白的表达。 结果 Morris水迷宫表明吸入3%浓度七氟烷6 h可导致成年小鼠认知功能损伤。免疫荧光实验表明吸入七氟烷后海马小胶质细胞被激活, 神经干细胞增殖功能被抑制; qPCR及Western blot实验表明七氟烷能增加M1型促炎性细胞因子mRNA水平以及Notch信号通路相关蛋白的表达。 结论 醒脑静注射液通过调节Notch信号通路减轻七氟烷诱导的学习记忆障碍，提示醒脑静注射液预处理可能是预防七氟烷致成年小鼠术后认知障碍的可行措施。 Abstract:OBJECTIVE To explore XingNaoJing injection how to alleviated postoperative cognitive dysfunction induced by sevoflurane and the Notch signaling pathway potential effect during above process. METHODS 36 male C57BL/6J mice aged of 8-12 weeks were randomly divided into three groups: control (Con), Sevoflurane (Sev), and sevoflurane+XingNaoJing injection(Sev+XNJ) groups, with 12 mice in each group. The cognitive abilities of mice in each group were tested using the Morris water maze. The hippocampal inflammation level in each group were tested using the immunofluorescence and qPCR. The neural stem cells proliferation function in each group were tested using the immunofluorescence. The relative protein expression of the Notch signaling pathway in each group were tested using the Western blotting. RESULTS The Morris water maze results showed that 3% sevoflurane exposure for 6 hours induced cognitive dysfunction in adult mice. Immunofluorescence results showed that hippocampal microglia were activated and neural stem cells proliferation was inhibited. qPCR and Western blot analysis showed that the mRNA levels of pro-inflammatory cytokines and the expression level of the Notch signaling pathway-related proteins in the hippocampus were upregulated by sevoflurane. CONCLUSION XingNaoJing injection mitigated sevoflurane-induced deficits in learning and memory by modulating the Notch signaling pathway. This research raised the possibility that XingNaoJing injection pretreatment might be a feasible measure to prevent postoperative cognitive deficits in adult mice induced by sevoflurane. -
图 1 醒脑静注射液改善七氟烷诱导的小鼠空间学习记忆障碍
注：A.第1~5天定向航行训练各组小鼠逃避潜伏期; B.第6天空间探索实验各组小鼠逃避潜伏期; C.空间探索实验各组小鼠平台穿越次数; 与对照组相比; D.空间探索实验各组小鼠典型游泳轨迹。与对照组相比, *P < 0.05，**P < 0.01;与Sev+XNJ组相比, #P < 0.05。x±s, n=8。
Figure 1. XingNaoJing injection improved sevoflurane-induced spatial learning and memory impairment in mice
图 2 醒脑静注射液对七氟烷引起的海马炎症反应的影响
注：与Sev组比较，*P < 0.05，**P < 0.01。x±s，n=4。
Figure 2. The effect of XingNaoJing injection on hippocampal inflammatory reaction caused by sevoflurane
图 3 醒脑静注射液对七氟烷诱导的神经干细胞增殖功能的影响
注：比例尺=100 μm。与Sev组相比, *P < 0.05, **P < 0.01。x±s, n=4。
Figure 3. The effect of XingNaoJing injection on neural stem cell proliferation function induced by sevoflurane
图 4 醒脑静注射液抑制七氟烷诱导的Notch/Hes1通路过度激活
注：与Con组相比, *P < 0.05, **P < 0.01;与Sev+XNJ组相比, #P < 0.05。x±s, n=4。
Figure 4. XingNaoJing injection suppress sevoflurane-induced Notch/Hes1 pathway over activation
表 1 引物序列
Table 1. Primer Sequences
引物 正向(5'-3') 反向(5'-3') TNF-α TTCTCATTCCTGCTTGTGG ACTTGGTGGTTTGCTACG IL-6 CCACCAAGAACGATAGTCAA TTTCCACGATTTCCCAGA IL-12 p35 GGACCAAACCAGCACAT CGCAGAGTCTCGCCATTA GAPDH TGCGACTTCAACAGCAACTC CTTGCTCAGTGTCCTTGCTG 
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