小檗碱对冈田酸拟AD大鼠空间学习记忆的改善作用及其机制

Effect of berberine on spatial learning and memory impairment in Alzheimer's disease model rats with okadaic acid and its mechanism

目的:探讨小檗碱(berberine,Ber)对冈田酸拟阿尔茨海默病(Alzheimer’s disease,AD)大鼠学习记忆的改善作用及其可能机制。方法:36只雄性SD大鼠随机分为对照组、模型组和Ber组,用侧脑室微量注射冈田酸(okadaic acid,OA,0.4 mmol/L,1.5μl/次,共3次)建立AD模型,Ber组是在模型制作前后灌胃(100mg/kg/d,共4周);采用Morris水迷宫测试大鼠的空间学习记忆能力,用Bieischowsky镀银改良法观察脑内神经原纤维缠结(neurofibrillary tangle,NFTs)的变化;用免疫组织化学方法检测pTau-Ser396和pTau-Ser404蛋白的表达。结果:与对照组相比,模型组大鼠各时间段的逃避潜伏期均延长,脑内出现较多NFTs,皮层和海马神经元pTau-Ser396/404的表达明显增高(P<0.01);Ber组大鼠潜伏期较模型组明显缩短,脑内NFTs的数量减少,pTau-Ser396/404的表达明显下调(P<0.01,P<0.05)。结论:小檗碱可明显改善AD模型大鼠空间学习记忆障碍,其机制可能与降低Tau磷酸化水平,减少NFTs有关。

Objective： To investigate the effect of berberine（Ber） on spatial learning and memory impairment in Alzheimer＇s disease model rats with okadaic acid and its preliminary mechanism.Methods： 36 male Sprague-Dawley rats were divided randomly into control group,model group and Ber group.The rats in model group were established by micro-injection okadaic acid（OA,0.4 mmol/L） into the lateral ventricle（1.5 μl/time,3 times）.The rats in Ber group were treated by berberine intragastric administration（100 mg/kg/d,4 weeks） before and after the model group was established.Morris water maze was used to test learning and memory ability of rats.The changes of neurofibrillary tangle（NFTs） were observed by Bielschowsky staining.Immunohistochemical method was performed to observe the expression of phosphorylation tau protein 396（pTau-Ser396） and 404（pTau-Ser404）.Results： Compared with control group,the escape latency in various time periods in model group was prolonged;more NFTs in model group were seen.The expression of pTau-Ser396/404 protein in the temporal cortex and the hippocampus of model group rats was increased（P〈0.01）.The escape latency in Ber group was obvious shortened,the number of NFTs was decreased and expression of pTau-Ser396/404 protein in Ber group was down-regulated compared with model group（P〈0.01,P〈0.05）.Conclusion： The spatial learning and memory impairment of AD model rats was improved by berberine.The mechanism was possibly due to down-regulation of phosphorylation tau protein and the decrease of NFTs.