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右美托咪定调控Sirt1/FOXO1介导的自噬通路对抑郁症大鼠认知功能的影响 被引量:2

Effects of dexmedetomidine on the cognitive function of depression rats by regulating Sirt1/FOXO1-mediated autophagy pathway
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摘要 目的:探究右美托咪定(DEX)调控沉默信息调节因子1(Sirt1)/叉头框蛋白O1(FOXO1)介导的自噬通路对抑郁症大鼠认知功能的影响。方法:将50只SD大鼠随机分为对照组、模型组、低剂量(2.5μg/kg)DEX(DEX-L)组、高剂量(10μg/kg)DEX(DEX-H)组及DEX-H+EX-527组(10μg/kg DEX+50μg/kg SIRT1抑制剂EX527),每组10只;通过连续56 d对大鼠进行慢性不可预知温和刺激构建抑郁症模型,DEX-L组、DEX-H组及DEX-H+EX-527组大鼠于第29天起进行腹腔注射相应药物,对照组及模型组腹腔注射等体积生理盐水,每天1次,共28 d;采用糖水偏好实验、强迫游泳实验、旷场实验及Morris水迷宫实验评估大鼠抑郁行为和认知功能;苏木精-伊红(HE)染色和尼氏(Nissl)染色观察海马神经元损伤情况;Western blot检测海马组织中Sirt1/FOXO1通路相关蛋白、LC3和beclin-1表达情况;免疫组化法检测Sirt1/FOXO1通路相关蛋白表达情况。结果:相较于对照组,模型组大鼠糖水偏爱度、水平运动得分、垂直运动得分、穿越平台次数、神经元数目、LC3-II/LC3-I比值及beclin-1、Sirt1和FOXO1表达水平显著降低,不动时间(FSIT)、逃避潜伏期和海马病理损伤程度显著增加(P<0.05);相较于模型组,DEX-L组及DEX-H组糖水偏爱度、水平运动得分、垂直运动得分、穿越平台次数、神经元数目及LC3-II/LC3-I比值及beclin-1、Sirt1和FOXO1表达水平显著增加,FSIT、逃避潜伏期和海马病理损伤程度显著降低(P<0.05);相较于DEX-H组,DEX-H+EX-527组糖水偏爱度、水平运动得分、垂直运动得分、穿越平台次数、神经元数目LC3-II/LC3-I比值及beclin-1、Sirt1和FOXO1表达水平显著降低,FSIT、逃避潜伏期和海马病理损伤程度显著增加(P<0.05)。结论:DEX通过激活Sirt1/FOXO1通路来促进抑郁症大鼠海马神经元自噬,改善认知功能。 AIM:To explore the effect of dexmedetomidine(DEX)-regulating silent information regulator 1(Sirt1)/forkhead transcription factor O1(FOXO1)-mediated autophagy pathway on the cognitive function of depression rats.METHODS:Fifty SD rats were randomly allocated into control group,model group,low dose of DEX(DEX-L)group(2.5μg/kg DEX),high dose of DEX(DEX-H)group(10μg/kg DEX)and DEX-H+EX-527 group(10μg/kg DEX+50μg/kg SIRT1 inhibitor EX527),with 10 per group.The depression rat model was established by chronic unpredictable mild stimulation for 56 consecutive days.The DEX-L,DEX-H and DEX-H+EX-527 groups were intraperitoneally injected with corresponding doses of drugs started from the 29th day.The control group and the model group were injected with the same amount of normal saline once per day for 28 days.Sugar water preference test,forced swimming test,open field test and Morris water maze test were used to evaluate the depressive behavior and cognitive function of rats.Hematoxylin-eosin(HE)and Nissl staining were used to observe the damage of hippocampal neurons.Western blot was used to detect the expression of Sirt1/FOXO1 pathway related proteins,and LC3-Ⅱ/-Ⅰand beclin-1 in hippocampus.Immunohistochemistry was used to detect the positive expression of Sirt1/FOXO1 pathway associated proteins.RESULTS:Compared with the control group,the sugar water preference,horizontal movement score,vertical movement score,number of crossing platforms,number of neurons,and the expression levels of LC3-Ⅱ/-Ⅰ,beclin-1,Sirt1 and FOXO1 were significantly reduced,while the forced swimming immobility time(FSIT),escape latency,and the degree of hippocampal pathological damage were significantly increased in the model group(P<0.05).DEX(DEX-L and DEX-H groups)rescued the sugar water preference,horizontal movement score,vertical movement score,number of crossing platforms and number of neurons,increased the expression of LC3-Ⅱ/-Ⅰ,beclin-1,Sirt1,and FOXO1,and reduced the FSIT,escape latency,and the degree of hippocampal pathological damage in a dose-dependent manner(P<0.05).Moreover,the effect of high dose of DEX was blocked by EX-527(P<0.05).CONCLUSION:DEX promotes autophagy of hippocampal neurons in depression rats by activating the Sirt1/FOXO1 signaling pathway,and thus improved cognitive function.
作者 邓志英 龙景新 顾晖 唐吉伟 皮倩 DENG Zhi-ying;LONG Jing-xin;GU Hui;TANG Ji-wei;PI Qian(Hunan Brain Hospital(The Second People's Hospital of Human Province),Changsha 410007,China)
出处 《中国病理生理杂志》 CAS CSCD 北大核心 2022年第5期858-865,共8页 Chinese Journal of Pathophysiology
基金 湖南省卫生健康委科研计划项目(No.20200582)。
关键词 右美托咪定 抑郁症 Sirt1/FOXO1信号通路 细胞自噬 认知功能 Dexmedetomidine Depression Sirt1/FOXO1 signaling pathway Autophagy Cognitive function
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