α7nAChR-HDAC6通路在右美托咪啶降低幼鼠七氟烷神经毒性中的作用

Dexmedetomidine ameliorates sevoflurane-induced neurotoxicity in neonatal mice via the pathway ofα7nAChR-HDAC6

目的:探讨α7烟碱型乙酰胆碱受体(α7nAChR)-组蛋白去乙酰化酶6(Histone deacetylase 6,HDAC6)通路在右美托咪啶降低幼鼠七氟烷神经毒性的作用。方法:7 d龄Sprague-Dawley(SD)大鼠随机分为5组(n=40):空白对照组(C组),七氟烷麻醉组(S组),右美托咪啶对照组(D组),七氟烷+右美托咪啶组(SD组),七氟烷+右美托咪啶+抑制剂MLA组(M组)。将幼鼠置于3%七氟烷培养箱2 h,连续3 d构建七氟烷模型。ELISA法检测幼鼠脑组织促炎因子(TNF-α、IL1β和IL-6)和脑损伤标志物(S-100β和NSE);尼式染色检测海马神经元CA1区存活情况;Western印迹检测海马α7nAChR和HDAC6蛋白表达;Y迷宫实验检测幼鼠认知水平。结果:S组幼鼠TNF-α、IL1β、IL-6和S-100β、NSE表达增加,α7nAChR降低,HDAC6增加,海马CA1区神经元存活降低,认知功能下降;右美托咪啶预处理降低七氟烷毒性;MLA可逆转右美托咪啶保护作用。结论:右美托咪啶降低七氟烷麻醉幼鼠神经毒性,其机制与α7nAChR-HDAC6通路有关。

Objective:To investigate the effect of dexmedetomidine on sevoflurane-induced neurotoxicity in neonatal mice via the pathway ofα7nAChR-HDAC6.Methods:Postnatal day 7 Sprague-Dawley(male)rats were randomly divided into 5 groups(n=40):blank control group(Group C),sevoflurane anesthesia group(Group S),right metoclopramide control group(Group D),sevoflurane and right metoclopramide group(Group SD),sevoflurane and right metoclopramide with inhibitor MLA group(group M).Neonatal mice were exposed to 3%sevoflurane 2 hours for 3 days with or without 25μg/kg dexmedetomidine intraperitoneal injection.The inflammatory cytokines(TNF-α,IL-6,IL-18 and IL-10)and brain injury factors(S-100βand NSE)were determined by ELISA.Nissl staining was performed to survey the number of survival neurons in hippocampal CA1 area.The expression ofα7nAChR and HDAC6 protein was analyzed by Western blot.The cognitive behavioral data of rats were collected at P41(the beginning of the adult stage)using Y-maze experiment.Results:There were statistically increased of TNF-α,IL1β,IL-6,S-100β,NSE,and HDAC6 protein expression,decreased of the number of suriving neurons in hippocampal CA1 area,expression ofα7nAChR and cognitive function in group S(P<0.05).Dexmedetomidine provided the neuroprotectives from sevoflurane injury.Moreover,the inhibitor MLA significantly eliminated the protective effect of dexmedetomidine on sevoflurane injury.Conclusion:Dexmedetomidine provide neuroprotection in a rat model of sevoflurane-induced neurotoxicity,which is related toα7nAChR-HDAC6 signaling pathway.