【摘要】 目的:研究淫羊藿苷(ICA)对精神分裂症模型大鼠认知功能的改善作用及机制。方法:将SD大鼠分为空白对照组、模型组和ICA低、中、高剂量组(15、30、60 mg/kg),除空白对照组外,其余组大鼠均腹腔注射N-甲基-D-天冬氨酸受体拮抗剂MK-801(0.2 mg/kg)复制精神分裂症模型,每天1次,连续14天。造模成功后,ICA各剂量组大鼠灌胃相应药物,空白对照组和模型组灌胃等体积水,每天1次,连续28天。采用Morris水迷宫实验、旷场实验、强迫游泳实验和Y迷宫实验观察大鼠行为学变化;采用Nissl法染色观察大鼠海马组织病理变化;采用酶联免疫吸附法(ELISA)检测大鼠脑组织中胆碱能相关指标[乙酰胆碱(Ach)、胆碱乙酰转移酶(ChAT)、乙酰胆碱酯酶(AchE)]的水平;采用实时荧光定量聚合酶链式反应(PCR)法检测大鼠脑组织中脑源性神经营养因子(BDNF)、细胞外信号调节蛋白激酶(ERK)、环磷腺苷反应元件结合蛋白(CREB)的mRNA的表达水平;采用Western blot法检测大鼠脑组织中BDNF、ERK、CREB蛋白和凋亡相关蛋白[B淋巴细胞瘤2(Bcl-2)及其相关X蛋白(Bax)、胱天蛋白酶3(Caspase-3)]的表达或磷酸化水平。结果:与空白组比较,模型组大鼠逃避潜伏期、T1～T3时段活动路程长度、累积不动时间和脑组织中Caspase-3蛋白的表达水平均显著增加或升高(P<0.05);穿台次数、交替率、海马组织中Nissl染色阳性神经元数以及脑组织中Ach和ChAT水平、Bcl-2/Bax比值、BDNF m RNA和蛋白的表达水平、ERK和CREB mRNA的表达水平、ERK1/2和CREB磷酸化水平均显著减少或降低(P<0.05)。与模型组比较,ICA高剂量组大鼠逃避潜伏期、T1～T3段活动路程长度、累积不动时间、Nissl染色阳性神经元数、脑组织中AchE水平和Caspase-3蛋白的相对表达量均显著减少或降低(P<0.05);穿台次数、交替率,脑组织中Ach和ChAT水平、Bcl-2/Bax比值、BDNF m RNA和蛋白的表达水平、ERK和CREB mRNA的表达水平、ERK1/2和CREB的磷酸化水平均显著增加或升高(P<0.05)。ICA低、中剂量组大鼠上述部分指标较模型组显著改善(P<0.05)。结论:ICA可改善精神分裂症模型大鼠的认知功能,其作用机制可能与调节胆碱能系统、抑制神经元凋亡、促进BDNF/ERK/CREB信号通路的表达有关。更多还原

【Abstract】 OBJECTIVE:To study the improvement effects of icariin(ICA)on cognitive function in schizophrenia model rats and its mechanism. METHODS:SD rats were divided into blank control group,model group,ICA low-dose,medium-dose and high-dose groups(15,30,60 mg/kg). Except for blank control group,other groups were given N-methyl-D-aspartate receptor antagonist MK-801(0.2 mg/kg)intraperitoneally to induce schizophrenia rats models,once a day,for consecutive 14 days. After modeling,ICA groups were intragastrically administered with the corresponding drugs,while blank control group and model group were intragastrically administered with the same volume of water,once a day,for consecutive 7 days. The behavioral changes of rats were detected by Morris water maze test,open field test, forced swimming test and Y maze test; the pathological changes of hippocampus were observed by Nissl staining; the levels of cholinergic indexes [acetylcholine(Ach), choline acetyltransferase(ChAT) and acetylcholinesterase(AchE)] in cerebral tissues were detected by ELISA. The expression of BDNF,ERK and CREB mRNA in cerebral tissue were detected by RT-PCR;expression or phosphorylation level of BDNF,ERK,CREB protein,apoptosis related proteins(Bcl-2,Bax and Caspase-3)were detected by Western blot. RESULTS:Compared with blank control group,escape latency,distance at T1-T3,cumulative immobility time and the expression of Caspase-3 protein in cerebral tissues were significantly increased in model group(P<0.05);the times of crossing platform,alternation rate,the number of Nissl staining positive neurons in hippocampus tissues,the levels of Ach and ChAT in cerebral tissues,Bcl-2/Bax ratio,mRNA and protein expression of BDNF,mRNA expression of ERK and CREB,the phosphorylation of ERK1/2 and CREB were significantly decreased(P<0.05).Compared with model group,escape latency,distance at T1-T3,cumulative immobility time,the number of Nissl staining positive neurons,AchE level in cerebral tissues and relative expression of Caspase-3 protein were significantly decreased in ICA high-dose group(P<0.05);the times of crossing platform,alternation rate,levels of Ach and ChAT in cerebral tissues,Bcl-2/Bax ratio,mRNA and protein expression of BDNF, m RNA expression of ERK and CREB, the phosphorylation of ERK1/2 and CREB were increased significantly(P<0.05). Above indexes in ICA low-dose and medium-dose groups were partially improved significantly than model group(P<0.05). CONCLUSIONS:ICA can improve cognitive function in schizophrenia model rats.Its mechanism may be related to regulating cholinergic system,inhibiting neuronal apoptosis,and promoting the expression of BDNF/ERK/CREB signaling pathway.更多还原