吡格列酮对阿尔茨海默病模型大鼠学习记忆障碍的改善及海马区BDNF、TrkB表达的作用

Effects of pioglitazone on improvement of learning and memory impairments and BDNF and Trk B expressions in hippocampus of brain in Alzheimer disease rats

目的探讨吡格列酮对β淀粉样蛋白(Aβ)25-35所致的阿尔茨海默病(AD)大鼠学习记忆障碍的改善作用及脑源性神经营养因子(BDNF)及酪氨酸激酶受体B(Trk B)海马区表达的作用。方法随机将40只SD大鼠分为痴呆模型组、对照组、吡格列酮高剂量组,吡格列酮低剂量组(每组10只),对照组双侧海马区注射生理盐水,其余3组以双侧海马CA1区注射Aβ25-35制备痴呆大鼠模型,造模后,高、低吡格列酮组分别用80 mg/kg及40 mg/kg,其余各组予生理盐水灌胃。Morris水迷宫检测痴呆大鼠学习记忆能力,免疫组化法检测双侧海马BDNF、Trk B阳性细胞的数目,Western blot的方法观察BDNF、Trk B表达量的变化。结果 Morris水迷宫检测显示:与模型组比较,吡格列酮治疗组潜伏期明显缩短(P<0.05),穿越平台次数明显增多(P<0.05),平台滞留时间明显延长(P<0.05)。免疫组化法检测显示模型组大鼠海马区BDNF及Trk B阳性细胞数较对照组明显减少,吡格列酮组较模型组明显增加(P均<0.05),低剂量组、高剂量组无明显差异。Western blot方法显示模型组大鼠海马区BDNF及Trk B表达量较对照组明显减少,吡格列酮组较模型组明显增加(P均<0.05),高、低剂量吡格列酮组无明显差异。结论海马CA1区注射Aβ25-35可致大鼠学习记忆障碍,吡格列酮可改善AD大鼠的学习记忆功能,其机制可能与调节脑内BDNF及特异性高亲和Trk B通路有关,从而为阿尔茨海默病的治疗提供新的理论依据。

Objective To investigate the effects of pioglitazone on learning and memory impairment in rats with Alzheimer disease induced by amyloid β-protein( Aβ) 25-35 and the expressions of brain-derived neurotrophic factor( BDNF) and tyrosine kinase receptor B( Trk B) in hippocampus. Methods Forty SD rats were randomly divided into four group( n =10 each) : control group,AD model group,pioglitazone high dose group and pioglitazone low dose group. In control group,normal saline was injected into hippocampus,and in the remaining 3 groups,AD model was established by injecting Aβ25-35 into bilateral hippocampal CA1 area. Two days after modeling,40 mg / kg pioglitazone and 80 mg / kg pioglitazone were respectively given by lavage in pioglitazone low dose and high dose groups,and equal volume of normal saline was given by lavage in control group and model group. Morris water maze test were used to detect the ability of learning and memory of rats. Immunohistochemistry method was used to detect the number of positive expression cells of BDNF and Trk B in bilateral hippocampus. Western blot method was used to semi-quantitatively analyze BDNF and Trk B expression levels. Results Morris water maze test showed that the incubation period significantly shortened( P < 0. 05); the times passing through platform significantly increase( P < 0. 05); the retention period at platform significantly prolonged in both pioglitazone treatment groups compared with model group( P < 0. 05); there were no significant differences in aforementioned indexes between both pioglitazone treatment groups( all P > 0. 05). Immunohistochemistry test showed that the number of BDNF-and Trk Bpositive expression cells in hippocampus significantly decreased in model group compared with control group( all P < 0. 05)and significantly increased in both pioglitazone treatment groups compared with model group( all P < 0. 05),while there were no significant differences between both pioglitazone treatment groups( all P > 0. 05). Western blot test showed that the BDNF and Trk B relative expression amounts in hippocampus decreased significantly in model group compared with control group and increased significantly in both pioglitazone treatment groups compared with model group( all P < 0. 05),while there were no significant differences between both pioglitazone treatment groups( all P > 0. 05). Conclusions Injecting Aβ25-35 into hippocampal CA1 area can cause learning and memory impairments. Pioglitazone can improve learning and memory functions of AD rats which might be associated with regulating BDNF and specific and high-affinity Trk B pathways in the brain,and this effect can provide a new theory evidence for the treatment of AD.