摘要
目的探讨丙戊酸钠对精神分裂大鼠环磷酸腺苷反应元件结合蛋白(CREB)/脑源性神经营养因子(BDNF)/酪氨酸激酶受体B(TrkB)通路及神经元损伤的影响。方法将50只雄性Wistar大鼠按随机数表法分为对照组、模型组、丙戊酸钠低剂量组、丙戊酸钠高剂量组和氯氮平组,每组10只。模型组、丙戊酸钠低剂量组、丙戊酸钠高剂量组和氯氮平组腹腔注射地卓西平(MK-801)制备精神分裂症模型。造模结束后24 h,丙戊酸钠低剂量组和丙戊酸钠高剂量组同时分别灌胃150 mg/kg和300 mg/kg的丙戊酸钠;氯氮平组灌胃20 mg/kg的氯氮平;对照组和模型组灌胃等体积生理盐水,1次/d,连续给予14 d。采用Morris水迷宫实验检测大鼠的学习和记忆能力,观察大鼠海马组织病理学情况,检测海马组织细胞凋亡情况,蛋白免疫印迹法检测海马组织中CREB、磷酸化-CREB(p-CREB)、BDNF、TrkB和磷酸化-TrkB(p-TrkB)蛋白表达水平。结果对照组大鼠海马组织细胞多且排列紧密,层次清晰;模型组和丙戊酸钠低剂量组大鼠海马组织排列紊乱,细胞明显肿胀、细胞核固缩、核碎裂;丙戊酸钠高剂量组和氯氮平组大鼠海马组织趋于正常,但见少量核固缩和核碎裂的细胞。与对照组比较,其余各组大鼠目标象限游泳时间、穿越平台次数、海马组织中CREB、p-CREB、BDNF、TrkB和p-TrkB蛋白表达水平降低,海马组织细胞凋亡率增加(P<0.05);与模型组相比,各丙戊酸钠剂量组和氯氮平组大鼠目标象限游泳时间、穿越平台次数、海马组织中CREB、p-CREB、BDNF、TrkB和p-TrkB蛋白表达水平增加,海马组织细胞凋亡率降低(P<0.05);且丙戊酸钠高剂量组大鼠目标象限游泳时间、穿越平台次数、海马组织中CREB、p-CREB、BDNF、TrkB和p-TrkB蛋白表达水平高于丙戊酸钠低剂量组,海马组织细胞凋亡率低于丙戊酸钠低剂量组(P<0.05);但作用没有氯氮平组显著(P<0.05)。结论丙戊酸钠可以缓解精神分裂症大鼠神经元损伤,抑制海马细胞凋亡,其作用机制可能与CREB/BDNF/TrkB通路激活有关。
Objective To investigate the effect of sodium valproate on cyclic cyclic adenosine monophosphate response element binding protein(CREB)/brain derived neurotrophic factor(BDNF)/tyrosine kinase receptor B(TrkB)Pathway and Neuronal Damage in Schizophrenic Rats.Methods Fifty male Wistar rats were randomly divided into control group,model group,low dose sodium valproate group,high dose sodium valproate group and clozapine group,with 10 rats in each group.The schizophrenia model was induced by intraperitoneal injection of dizocilpine(MK-801)in model group,low dose sodium valproate group,high dose sodium valproate group and clozapine group.24 hours after modeling,the rats in the low dose sodium valproate group and high dose sodium valproate group were given 150 mg/kg and 300 mg/kg sodium valproate by gavage respectively,and the rats in the clozapine group were given clozapine 20 mg/kg by gavage.The rats in the control group and the model group were given the same volume of normal saline by gavage,once a day for 14 days.Morris water maze test was used to test the learning and memory ability of rats,and the pathological changes of hippocampus of rats were observed,the apoptosis of hippocampal cells was detected.Western blot was used to detect the expression of CREB,phosphorylation-CREB(p-CREB),BDNF,TrkB and phosphorylation-TrkB(p-TrkB)protein in hippocampus tissue.Results In the control group,the hippocampal cells were numerous and closely arranged with clear layers.The hippocampal tissue of rats in model group and low dose sodium valproate group was disordered,and cells were obviously swollen,and pyknosis and nuclear fragmentation were observed.The hippocampus tissue of rats in high dose sodium valproate group and clozapine group tended to be normal,but a small number of nuclear pyknosis and nuclear fragmentation cells were observed.Compared with the control group,the swimming time in target quadrant,times of crossing platform,expression levels of CREB,p-CREB,BDNF,TrkB and p-TrkB protein in hippocampus tissue of rats in other groups were decreased,and the apoptosis rate of hippocampal cells increased(P<0.05).Compared with the model group,the swimming time in target quadrant,times of crossing platform,expression levels of CREB,p-CREB,BDNF,TrkB and p-TrkB protein in hippocampus tissue of rats in each sodium valproate dose group and clozapine group were increased,and the apoptosis rate of hippocampal cells decreased(P<0.05).The swimming time in target quadrant,times of crossing platform,expression levels of CREB,p-CREB,BDNF,TrkB and p-TrkB protein in hippocampus tissue of rats in the high dose sodium valproate group were higher than those in low dose sodium valproate group,and apoptosis rate of hippocampus cells was lower than that of low dose sodium valproate group(P<0.05).Finally,the positive effects of clozapine group were all greater than that in the other groups(P<0.05).Conclusion Sodium valproate can alleviate neuronal injury in schizophrenic rats,inhibit apoptosis of hippocampal cell,and its mechanism may be related to the activation of CREB/BDNF/TrkB pathway.
作者
吴乃斌
李莉
崔璐莎
李鑫
孙妍
Wu Naibin;Li Li;Cui Lusha(Department of Psychiatry,Kailuan Tangjiazhuang Hospital,Tangshan,Hebei 063100;Kailuan Mental Health Center,Tangshan,Hebei 063000,China)
出处
《四川医学》
CAS
2021年第6期579-584,共6页
Sichuan Medical Journal
基金
河北省医学科学研究课题计划项目(编号:20201275)。
