右美托咪定通过激活SIRT1/BDNF信号通路改善新生大鼠缺氧缺血性脑损伤所致认知障碍

Dexmedetomidine Improves Cognitive Impairment Induced by Hypoxic-ischemic Brain Damage in Neonatal Ratsby Activating SIRT1/BDNF Signaling Pathway

目的探讨右美托咪定(Dexmedetomidine,Dex)对缺氧缺血性脑损伤(hypoxic-ischemic brain damage,HIBD)新生大鼠认知障碍的作用及其机制。方法采用改良Rice法复制HIBD大鼠模型,将新生大鼠分为对照组(Control组)、模型组(HIBD组)、Dex组(腹腔注射100μg/kg右美托咪定)、右美托咪定+SIRT1抑制剂组(Dex+EX527组,腹腔注射100μg/kg右美托咪定+侧脑室注射10μg EX527),对大鼠进行神经功能评分,检测大鼠学习记忆功能、脑梗死面积、神经元凋亡及海马组织突触后致密蛋白-95(postsynaptic dense protein-95,PSD95)、沉默信息调节因子1(silent information regulator 1,SIRT1)、cAMP应答元件结合蛋白(cAMP response element binding protein,CREB)、磷酸化CREB(pCREB)、脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)表达。结果与Control组比较,HIBD组大鼠在第2、4、6天(D2、D4、D6)逃避潜伏期显著延长,空间探索时间明显增加,穿越平台次数明显减少,脑梗死面积与神经功能评分、神经元凋亡率显著增加,海马组织PSD95阳性表达率及SIRT1、pCREB、BDNF蛋白表达水平显著降低(均P<0.05);与HIBD组比较,Dex组大鼠在D2、D4、D6逃避潜伏期明显缩短(均P<0.05),空间探索时间明显减少,穿越平台次数明显增加,脑梗死面积与神经功能评分、神经元凋亡率显著降低,海马组织PSD95阳性表达率及SIRT1、pCREB、BDNF蛋白表达水平显著升高(均P<0.05);右美托咪定改善HIBD新生大鼠认知障碍的作用被EX527抑制。结论右美托咪定可通过激活SIRT1/BDNF信号通路改善HIBD新生大鼠神经损伤及认知障碍。

Objective To investigate the effect and mechanism of Dexmedetomidine(Dex)on cognitive impairment in neonatal rats with hypoxic-ischemic brain damage(HIBD).Methods The HIBD rat model was established by the modified Rice method,and the rats were divided into Control group,model group(HIBD group),Dex group(intraperitoneal injection of 100μg/kg Dexmedetomidine),and Dexmedetomidine+SIRT1 inhibitor group(Dex+EX527,intraperitoneal injection of 100μg/kg Dexmedetomidine+lateral ventricle injection of 10 pg EX527).Rats were scored for neurological function.The learning and memory function,cerebral infarction area,neuronal apoptosis and the expression of postsynaptic dense protein-95(PSD95),silent information regulator 1(SIRT1),cAMP response element binding protein(CREB),phosphorylated(pCREB)and brain derived neurotrophic factor(BDNF)in hippocampus area were detected.Results Compared with the Control group,the escape latencies on day 2,4,6(D2,D4,D6)in the HIBD group were obviously prolonged,the space exploration time was obviously increased.The number of crossing the platform was obviously decreased.The cerebral infarction area,the neurological function score,and neu-ron apoptosis rate were obviously increased.The positive expression rate of PSD95 and the expression levels of SIRT1,pCREB and BDNF in hippocampus were obviously decreased(all P<0.05);compared with the HIBD group,the escape latencies on D2,D4,D6 of rats in the Dex group were obviously shortened(P<0.05).The space exploration time was obviously reduced.The number of crossing platforms was obviously increased.The cerebral infarction area,the neurological function score,and neuron apoptosis rate were obviously decreased.The positive expression rate of PSD95 and the expression levels of SIRT1,pCREB and BDNF in hippocampus were obviously increased(all P<0.05).The effects of Dexmedetomidine on cognitive impairment in HIBD neonatal rats were inhibited by EX527.Conclusion Dexmedetomidine can improve neurological damage and cognitive impairment in HIBD neonatal rats by activating SIRT1/BDNF signaling pathway.