海马组蛋白脱乙酰基酶在大鼠PND中的作用及其与PSD95的关系

Role of hippocampal histone deacetylases in perioperative neurocognitive disorders in rats and the relationship with PSD95

目的评价组蛋白脱乙酰基酶(HDACs)在大鼠围术期神经认知紊乱(PND)中的作用及与突触后致密蛋白95(PSD95)的关系。方法清洁级健康雄性SD大鼠60只,10~14周龄,体重250~280 g,采用随机数字表法分为3组(n=20):对照组(C组)、手术组(S组)和HDAC抑制剂MS-275组(MS-275组)。S组3%七氟烷麻醉下行剖腹探查术,MS-275组于剖腹探查术前0.5 h腹腔注射MS-27510 mg/kg。于术前1 d、术后1、3和7 d时行水迷宫实验。于术后1 d时,每组随机处死10只大鼠,取海马组织,分别采用Western blot法和RT-PCR法检测海马HDAC1-3、PSD95及其mRNA的表达水平。采用Nissl染色确定海马神经元密度。结果与C组比较,S组术后逃避潜伏期延长,穿越原平台次数减少,海马神经元密度降低,HDAC2及其mRNA表达上调,PSD95及其mRNA表达下调(P<0.05或0.01)。与S组比较,MS-275组术后逃避潜伏期缩短,穿越原平台次数增加,海马神经元密度升高,HDAC2及其mRNA表达下调,PSD95及其mRNA表达上调(P<0.05或0.01)。3组海马组织HDAC1、HDAC3及其mRNA表达水平比较差异无统计学意义(P>0.05)。结论海马HDAC2可能通过下调PSD95表达,参与大鼠PND的病理生理机制。

Objective To evaluate the role of hippocampal histone deacetylases(HDACs)in perioperative neurocognitive disorders(PND)and the relationship with postsynaptic dense protein 95(PSD95)in rats.Methods Sixty clean-grade healthy male Sprague-Dawley rats,aged 10-14 weeks,weighing 250-280 g,were divided into 3 groups(n=20 each)using a random number table method:control group(group C),surgery group(group S)and HDAC inhibitor MS-275 group(group MS-275).Exploratory laparotomy was performed under 3%sevoflurane anesthesia in group S.MS-27510 mg/kg was intraperitoneally injected at 0.5 h before exploratory laparotomy in group MS-275.Morris water maze tests were performed on 1 day before surgery and 1,3 and 7 days after surgery.Ten rats were sacrificed on 1 day after surgery,and hippocampal tissues were obtained for determination of the expression of HDAC1-3 and PSD95 protein and mRNA by Western blot and real-time polymerase chain reaction,respectively.The density of hippocampal neurons was determined by the Nissl staining.Results Compared with group C,the postoperative escape latency was significantly prolonged,the number of crossing the original platform was decreased,the density of hippocampal neurons was decreased,the expression of HDAC2 protein and mRNA was up-regulated,and the expression of PSD95 protein and mRNA was down-regulated in group S(P<0.05 or 0.01).Compared with group S,the postoperative escape latency was significantly shortened,the number of crossing the original platform was increased,the density of hippocampal neurons was increased,the expression of HDAC2 protein and mRNA was down-regulated,and the expression of PSD95 protein and mRNA was up-regulated in group MS-275(P<0.05 or 0.01).There was no significant difference in the expression of HDAC1 and HDAC3 protein and mRNA among the three groups(P>0.05).Conclusion HDAC2 is involved in the pathophysiological mechanism of PND by down-regulating the expression of PSD95 in rats.