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作 者:万航娟 罗丽 何蔚[2,3,4] WAN Hang-juan;LUO Li;HE Wei(Postgraduate students of Grade 2019,Gannan Medical University;Department of Pharmacology,Gannan Medical University;Key Laboratory of Cerebrovascular Pharmacology of Jiangxi Province;Key Laboratory of Ministry of Education for Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases,Ganzhou,Jiangxi 341000)
机构地区:[1]赣南医学院 [2]赣南医学院药理学教研室 [3]江西省脑血管药理重点实验室 [4]心脑血管疾病防治教育部重点实验室,江西赣州341000
出 处:《赣南医学院学报》2022年第5期443-449,共7页JOURNAL OF GANNAN MEDICAL UNIVERSITY
基 金:江西省卫生健康委员会科技计划项目(SKJP-202210927);赣南医学院研究生创新专项资金项目(YC2020-X002)。
摘 要:目的:研究欧前胡素对侧脑室注射Aβ_(1-42)致阿尔茨海默病(Alzheimer´s disease,AD)模型小鼠海马组织中沉默信息调节因子1(SIRT1)和磷酸化蛋白激酶RNA样内质网激酶(PERK)/真核翻译起始因子2α(eIF2α)及CCAAT/增强子结合蛋白同源蛋白(CHOP)蛋白表达的影响。方法:采用10μM Aβ_(1-42)诱导离体小鼠脑片损伤模型,观察欧前胡素对离体脑片乳酸脱氢酶(LDH)活性,用MTT法检测脑片活力,并用ELISA检测脑片中SIRT1和葡萄糖调节蛋白78(GRP78)的含量。用Aβ_(1-42)对雄性小鼠进行脑室内注射制备AD小鼠模型,欧前胡素(2.5 mg·kg^(-1)和5.0 mg·kg^(-1))于造模当天通过腹腔注射给药,1次·d^(-1),连续给药13 d,取小鼠的海马组织,用Western Blot检测海马中SIRT1、内质网应激相关分子GRP78、PERK、磷酸化PERK(p-PERK)、eIF2α、磷酸化eIF2α(p-eIF2α)和CHOP的蛋白表达。结果:与AD模型组相比,欧前胡素可减轻脑片损伤,增加脑片活力,提高SIRT1的水平,降低GRP78的含量。同时,欧前胡素可上调SIRT1的表达,下调GRP78、p-PERK、p-eIF2α和CHOP的表达,降低p-PERK/PERK和p-eIF2α/eIF2α的比值。结论:欧前胡素上调SIRT1表达,调控PERK/eIF2α的磷酸化激活,可能与欧前胡素对AD模型小鼠的神经保护作用有关。Objective:To investigate the effects of imperatorin on the SIRT1 and phosphorylated PERK/eIF2αand CCAAT/enhancer-binding protein homologous protein(CHOP)expressions in a mouse model of Alzheimer's disease(AD)induced by intracerebroventricular injection of Aβ_(1-42).Methods:Mouse brain slices were incubated with 10μM Aβ_(1-42) to established AD model in vitro.The neuronal damage was detected by LDH activity assay,the brain slices viability was measured by MTT assay,and the silent information regulator 1(SIRT1)and the glucose-regulated protein 78(GRP78)levels were observed by ELISA.Male mouse model of Alzheimer's disease was established by injection of Aβ_(1-42) into the lateral cerebroventricles.Imperatorin(2.5 and 5.0 mg·kg^(-1))was injected by intraperitoneally after surgery once a day for 13 consecutive days.The protein expression of SIRT1,endoplasmic reticulum stress-related molecule GRP78,protein kinase RNA-like endoplasmic reticulum kinase(PERK),phosphorylated PERK(p-PERK),eukaryotic translation initiation factor 2α(eIF2α),phosphorylated eIF2α(p-eIF2α),and CHOP in the hippocampus tissue of the mice were detected by western blot.Results:Compared with the AD model group,pretreatment of brain slices with imperatorin significantly reduced the activity of LDH,increased the brain slices viability and the levels of SIRT1,and decreased the GRP78 contents.Meanwhile,imperatorin treatment significantly up-regulated the expressions of SIRT1,down-regulated the protein expressions of GRP78,p-PERK,p-eIF2αand CHOP,and decreased the ratio of p-PERK/PERK and p-eIF2α/eIF2αin the AD mice induced by Aβ_(1-42).Conclusion:Imperatorin up-regulates the expression of SIRT1 and regulates the phosphorylated activation of PERK/eIF2α,which may be related to the neuroprotective effects of imperatorin on AD model mice.
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