奥氮平对精神分裂症大鼠认知功能和神经元损伤影响中PI3K/Akt信号通路的作用

Based on PI3K/Akt signaling pathway to explore the effects of olanzapine on cognitive function and neuronal damage in schizophrenic rats

目的 探讨奥氮平对老年精神分裂大鼠认知功能和神经元损伤的影响中PI3K/Akt信号通路的作用。方法 10周龄SD大鼠随机分为空白对照组(n=12)和老年精神分裂模型组(n=48)。老年精神分裂模型组动物经腹腔注射地卓西平马来酸盐(MK-801)0.2 mg/(kg·d),连续14 d后,进行一般行为学评价以观察模型是否制作成功。将模型制作成功大鼠随机分为模型组和奥氮平低、中、高剂量组[10、20、40 mg/(kg·d)],每组12只,连续给药21 d。采用Sams Dodd和Hoffman标准对刻板行为进行评分,Morris水迷宫对大鼠进行认知评价,采用ELISA测定血清中白细胞介素-6(IL-6)、肿瘤坏死因子α(TNF-α)水平。利用乙酰胆碱酯酶(AchE)活性测定试剂盒检测脑组织中乙酰胆碱(Ach)、AchE的活性。Real-time PCR检测大鼠脑组织PI3K、Akt、哺乳动物雷帕霉素靶蛋白(mTOR) mRNA的表达水平。结果 与模型组相比,奥氮平低、中、高剂量组大鼠的刻板行为及共济失调评分、逃避潜伏期、跨越平台次数、血清中IL-6、TNF-α水平、脑组织AchE、、磷酸化Akt (p-Akt)蛋白表达减少(P<0.05,P<0.01);而脑组织Ach、PI3K、mTOR及磷酸化mTOR (p-mTOR)和磷酸化PI3K(p-PI3K)表达量增加(P<0.05,P<0.01),奥氮平低剂量组Akt含量增加;与模型组相比,奥氮平低、中、高剂量组大鼠脑组织中Akt和mTOR mRNA表达水平下调(P<0.05,P<0.01),奥氮平中、高剂量组大鼠脑组织中PI3K表达水平下调(P<0.05,P<0.01)。结论 奥氮平可降低刻板行为及共济失调评分、逃避潜伏期、跨越平台次数、血清IL-6、TNF-α水平和脑组织AchE,增加Ach含量,通过调节PI3K/Akt信号通路对老年精神分裂症起到治疗作用。

Objective To explore olanzapine effect on the cognitive function and neuronal damage of aged schizophrenic rats based on the PI3 K/Akt signaling pathway. Methods Ten-week-old SD rats were randomly divided into a blank control group(n=12) and a modeling intervention group(n=48). The modeling group were injected with didroxapine maleate [MK-801,0.2 mg/(kg·d)] for 14 days. And the model was evaluated by general behavioral studies to determine the success of model building. The model rats were randomly divided into model group and low, medium, and high dose olanzapine groups [10, 20, 40 mg/(kg·d)], each with 12 rats. The control group and model group were given distilled water;the low, medium, and high dose olanzapine groups were given olanzapine for 21 days. The stereotyped lines were scored by the standard of Sams Dodd and Hoffman, the cognitive evaluation of the rats was performed by the Morris water maze, and the levels of interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in the serum were determined by ELISA. The activities of dihydrokaempferol(Ach) and acetyl cholinesterase(AchE)in brain tissue were detected by acetylcholinesterase activity assay kit. Rat brain tissue PI3 K, Akt, mammalian target of rapamycin(mTOR) mRNA expression levels were detected by Real-time PCR. Results Compared with the model group, the stereotyped behavior and ataxia scores, escape latency, number of crossing platforms, serum levels of IL-6, TNF-α, AchE, phosphorylated PI3 K(p-PI3 K), phosphorylated Akt(p-Akt) protein expression decreased(P<0.05 or P<0.01), while brain tissue Ach, PI3 K, mTOR and phosphorylated mTOR(p-mTOR) protein content increased(P<0.05 or P<0.01) in the low, medium and high dose olanzapine groups. The content of Akt was increased in the low-dose group. Compared with the model group, Akt and mTOR mRNA in the brain tissue of rats in the low, medium, and high-dose alanzapine groups expression levels were down-regulated(P<0.05 or P<0.01). PI3 K mRNA in the brain tissue of rats in the low, medium, and high-dose alanzapine groups expression levels were down-regulated(P<0.05 or P<0.01). Conclusion Olanzapine can reduce stereotyped behavior and ataxia scores, escape latency, number of crossing platforms, IL-6, TNF-α, AchE and increase Ach content and regulate the PI3 K/Akt signaling pathway to relieve the schizophrenia.