选择性组蛋白脱乙酰酶抑制剂MS-275对氯化锂-匹鲁卡品致痫大鼠的神经保护作用及机制研究

Neuroprotective effects and mechanisms of selective histone deacetylases inhibitor MS-275 on lithium-pilocarpine induced seizures in rats

目的 探讨选择性组蛋白脱乙酰酶抑制剂MS-275对癫痫所致脑损伤的保护作用及可能机制.方法 将75只Sprague-Dawley大鼠随机分为5组:对照组、匹鲁卡品组、治疗I组(致痫后7d连续腹腔注射MS-275,20 mg/kg,1次/d)、治疗Ⅱ组(致痫后7d连续腹腔注射MS-275,40 mg/kg,1次/d)、MS-275预处理组.通过氯化锂-匹鲁卡品诱导大鼠癫痫发作.观察各组大鼠行为学差异;致痫后72 h Nissl染色观察各组大鼠海马区的病理学改变并计数海马CA1及CA3区的神经元存活数,免疫组织化学法测定大鼠海马CA1及CA3区组蛋白乙酰化水平;致痫后11d,Morris水迷宫测定大鼠的认知功能.结果 与匹鲁卡品组相比,MS-275预处理组大鼠出现癫痫持续状态的潜伏期可延长且致痫大鼠死亡率降低(P<0.05).与匹鲁卡品组相比,治疗Ⅰ组及治疗Ⅱ组大鼠海马CA1、CA3区神经元变性的程度降低,治疗Ⅰ组及治疗Ⅱ组大鼠海马CA1及CA3区的组蛋白乙酰化水平比匹鲁卡品组高(P<0.05).与对照组、MS-275预处理组、治疗Ⅰ、Ⅱ组比较,匹鲁卡品组的逃避潜伏期均出现明显延长(P<0.05).结论 MS-275对氯化锂-匹鲁卡品致痫后大鼠海马的神经元损伤、组蛋白脱乙酰化程度以及大鼠的认知功能下降有改善作用,对大鼠癫痫所致脑损伤有一定的保护作用,其作用机制可能与其抗炎作用相关.

Objective To investigate the neuroprotective ffets and mechanisms of selective histone deacetylases inhibitor MS-275 on rats after seizures.Methods A total of 75 rats were randomly divided into 5 groups for trealment:control group,pilocearpine group,treatment group I(administered with MS-275,20mg/kg.once a day,intraperitoneally in 7 consecutive days),treatment group I(administered with MS-275,40mg/kg,once a day,intraperitoncally in 7 consccutive days),MS-275 pretreatment group.We used lithium and pilocarpin to induce seizures.Behaviors of rats in each group were observed.At 72 hours afer seizures,Nissl staining and immunohistochemical were respectively used to evaluate the loss of neurons and histone acetylation levels of hippocampal CA1 and CA3 regions in each group.Escape latency in the control group,treatment group I,treatment group I and MS-275 pretreatment group were longer than pilocarpine group(P<0.05).Results Compared with the pilocarpine group,rats in MS-275 pretreatment group could delay pilocarpine-induced scizures and reduce mortality(P<0.05).Degree of neuronal loss and degeneration in both treatment groupI and treatment group I were reduced compared with the pilocarpine group(P<0.05)and the level of histone acetyation in hippocampal CAI and CA3 regions of the rats were increased compared with the pilcrpine group(P<0.05).Conclusion HDACs inhibitors MS-275 can improve the neuronal damage,histone deacetylation of rats’brain and rats cognitive decline,which can exert an neuroprotective ffet on rats after seizures,whose mechanism may be related to its antinflammatory effect.