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目的:探讨内质网应激在慢性间歇低氧幼鼠脑损害中的作用机制及salubrinal的干预作用。方法:取SPF级健康雄性SD幼鼠64只,随机分为8组:间歇低氧(intermittent hypoxia,IH)2、4周组(2IH、4IH),对照(control,C)2、4周组(2C、4C),Salubrinal(SAL)干预2、4周组(2SAL、4SAL),二甲基亚砜(DMSO)溶剂对照2、4周组(2DMSO、4DMSO),每组8只。八臂迷宫测试各组幼鼠参考记忆错误(RME)、工作记忆错误(WME)及总错误(TE)次数,观察海马神经元凋亡变化,测定超氧化物歧化酶(SOD)活性,及内质网应激标志物C/EBP同源蛋白(CHOP)、磷酸化真核翻译起始因子2α(p-e IF2α)和磷酸化蛋白激酶R样内质网激酶(p-PERK)的蛋白水平。结果:与相应对照2C、4C组比较,间歇低氧2IH、4IH组幼鼠的RME、WME和TE升高(P<0.01),海马神经元凋亡指数(AI)升高(P<0.01),SOD活性下降(P<0.01),p-PERK和CHOP蛋白水平升高(P<0.01),p-e IF2α蛋白水平下降(P<0.05),4周组最明显;与对应间歇性低氧2IH、4IH组比较,药物干预组2SAL、4SAL组RME、WME和TE次数下降(P<0.05),AI下降(P<0.01),SOD活性升高(P<0.01),p-e IF2α的蛋白水平升高(P<0.01),CHOP表达下降(P<0.01)。结论:慢性间歇低氧可上调记忆相关脑区p-PERK表达,启动内质网应激,从而诱导CHOP所介导的细胞凋亡,可能在慢性间歇低氧所致脑损伤中起重要作用。Salubrinal选择性抑制e IF2α去磷酸化,下调CHOP蛋白的水平,提高SOD活性,从而缓解内质网应激,减轻氧化应激,减少细胞凋亡。
Objective: To explore the mechanism of endoplasmic reticulum stress in the brain of rats with chronic intermittent hypoxia and the intervention of salubrinal. Methods: Sixty-four healthy SPF male SD rats were randomly divided into 8 groups: 2, 4, and 4 weeks of intermittent hypoxia (IH), control (C) (2C, 4C) and Salubrinal (SAL) intervention groups of 2, 4 weeks (2SAL, 4SAL) and dimethylsulfoxide (DMSO) solvent control groups of 2 and 4 weeks (2DMSO, 4DMSO). Eight-armed maze was used to test the changes of RME, WME and TE in each group. The changes of apoptosis in hippocampal neurons were observed, and the activity of superoxide dismutase (SOD) C / EBP homology protein (CHOP), phospho-eukaryotic translation initiation factor 2 alpha (peIF2 alpha) and phospho-protein kinase R-like endoplasmic reticulum kinase (p-PERK) Results: Compared with the corresponding control groups 2C and 4C, RME, WME and TE in intermittent hypoxia 2IH and 4IH groups were significantly increased (P <0.01), and the apoptosis index (AI) of hippocampal neurons increased (P <0.01) (P <0.01). The protein level of peIF2α decreased (P <0.05), and the level of pe IF2α protein was the highest in 4 weeks group. Compared with the corresponding groups of intermittent hypoxia and 2IH, Compared with 4IH group, the number of RME, WME and TE in 2SAL and 4SAL groups decreased (P <0.05), AI decreased (P <0.01), SOD activity increased (P <0.01) and peIF2α protein level increased P <0.01), CHOP expression decreased (P <0.01). CONCLUSION: Chronic intermittent hypoxia can up-regulate the expression of p-PERK in memory-related brain regions, activate endoplasmic reticulum stress and induce CHOP-mediated apoptosis, which may play an important role in chronic intermittent hypoxic-induced brain injury. Salubrinal selectively inhibits eIF2alpha dephosphorylation, down-regulates CHOP protein levels, and increases SOD activity, thereby alleviating endoplasmic reticulum stress, reducing oxidative stress, and decreasing apoptosis.