奥氮平通过PI3K/Akt通路对精神分裂症模型大鼠发挥神经保护作用的研究

Research on Olanzapine's Neuroprotective Effect on Schizophrenic Model Rats Through PI3K/Akt Pathway

目的:探讨奥氮平是否通过磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)通路对精神分裂症模型大鼠发挥神经保护作用。方法:建立精神分裂症模型大鼠,随机分为模型组、LY294002(PI3K/Akt通路抑制剂)组、奥氮平组及奥氮平+LY294002组,每组12只;另取12只SD大鼠设为对照组。分组处理后,对大鼠刻板行为及共济失调进行评分;苏木精-伊红染色检测大鼠脑部海马组织神经元病理变化;水迷宫实验检测大鼠认知功能;酶联免疫吸附法检测大鼠血清白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)水平;蛋白免疫印迹法检测脑组织PI3K/Akt通路相关蛋白表达情况。结果:与对照组相比,模型组大鼠海马组织呈现神经元细胞数量减少,排列稀疏,细胞核固缩,胞质、核仁结构不清晰,染色深,细胞出现凋亡、坏死等病理损伤;刻板行为评分、共济失调评分和血清IL-6、TNF-α水平明显升高,水迷宫实验平均逃避潜伏期明显延长,穿越原平台位置次数明显减少,脑组织p-PI3K/PI3K及p-Akt/Akt表达明显降低,差异均有统计学意义(P<0.05)。与模型组相比,奥氮平组大鼠海马组织神经元病理损伤减轻,刻板行为评分、共济失调评分和血清IL-6、TNF-α水平明显降低,水迷宫实验平均逃避潜伏期明显缩短,穿越原平台位置次数明显增加,脑组织p-PI3K/PI3K及p-Akt/Akt明显升高,差异均有统计学意义(P<0.05)。与模型组相比,LY294002组大鼠海马组织神经元病理损伤加重,刻板行为评分、共济失调评分和血清IL-6、TNF-α水平明显升高,水迷宫实验平均逃避潜伏期明显延长,穿越原平台位置次数明显减少,脑组织p-PI3K/PI3K及p-Akt/Akt表达明显降低,差异均有统计学意义(P<0.05)。与LY294002组相比,奥氮平+LY294002组大鼠海马组织神经元病理损伤减轻,刻板行为评分、共济失调评分和血清IL-6、TNF-α水平明显降低,水迷宫实验平均逃避潜伏期明显缩短,穿越原平台位置次数明显增加,脑组织p-PI3K/PI3K及p-Akt/Akt表达明显升高,差异均有统计学意义(P<0.05)。与奥氮平组相比,奥氮平+LY294002组大鼠海马组织神经元病理损伤加重,刻板行为评分、共济失调评分和血清IL-6、TNF-α水平明显升高,水迷宫实验平均逃避潜伏期明显延长,穿越原平台位置次数明显减少,脑组织p-PI3K/PI3K及p-Akt/Akt表达明显降低,差异均有统计学意义(P<0.05)。结论:奥氮平可通过激活PI3K/Akt通路对精神分裂症大鼠发挥神经保护作用。

OBJECTIVE:To probe into whether olanzapine plays the role of neuroprotection on schizophrenic model rats through phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)pathway.METHODS:Schizophrenic model rats were established and divided into model group,LY294002(PI3K/Akt pathway inhibitor)group,olanzapine group and olanzapine+LY294002 group,with 12 rats in each group;another 12 SD rates were set as control group.After grouping,the rats'stereotyped behavior and ataxia were scored;hematoxylin-eosin staining was used to detect the pathological changes of hippocampal neurons of the rat brain;the water maze test was used to detect the cognitive function;enzyme linked immunosorbent assay was used to detect the serum interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)levels;Western blotting was used to detect the expression of PI3K/Akt pathway-related proteins in brain tissue.RESULTS:Compared with the control group,the hippocampus of model group showed a reduction in the number of neuronal cells,sparse alignment,shrinkage of the nucleus,unclear cytoplasm and nucleolus structure,deep staining,pathological damage like cell apoptosis and necrosis;scores of stereotyped behavior and ataxia,serum IL-6 and TNF-αlevels were significantly increased,the average escape latency of water maze test was significantly prolonged,the frequency of crossing original platform was significantly reduced,the brain tissue p-PI3K/PI3K and p-Akt/Akt were significantly decreased,with statistically significant differences(P<0.05).Compared with the model group,the pathological damage of hippocampal neurons of olanzapine group was relieved,scores of stereotyped behavior and ataxia,serum IL-6 and TNF-αlevels were significantly reduced,the average escape latency of water maze test was significantly shortened,the frequency of crossing original platform was significantly increased,brain tissue p-PI3K/PI3K and p-Akt/Akt were significantly increased,with statistically significant differences(P<0.05).Compared with the model group,the pathological damage of hippocampal neurons of LY294002 group was aggravated,scores of stereotyped behavior and ataxia,serum IL-6 and TNF-αlevels were significantly increased,the average escape latency of water maze test was significantly prolonged,the frequency of crossing original platform was significantly reduced,the brain tissue p-PI3K/PI3K and p-Akt/Akt were significantly decreased,with statistically significant differences(P<0.05).Compared with the LY294002 group,the pathological damage of hippocampal neurons of olanzapine+LY294002 group was relieved,scores of stereotyped behavior and ataxia,serum IL-6 and TNF-αlevels were significantly reduced,the average escape latency of water maze test was significantly prolonged,the frequency of crossing original platform was significantly increased,brain tissue p-PI3K/PI3K and p-Akt/Akt were significantly increased,with statistically significant differences(P<0.05).Compared with the olanzapine group,the pathological damage of hippocampal neurons of olanzapine+LY294002 group was aggravated,scores of stereotyped behavior and ataxia,serum IL-6 and TNF-αlevels were significantly increased,the average escape latency of water maze test was significantly prolonged,the frequency of crossing original platform was significantly reduced,the brain tissue p-PI3K/PI3K and p-Akt/Akt were significantly decreased,with statistically significant differences(P<0.05).CONCLUSIONS:Olanzapine can play the role of neuroprotection on schizophrenic model rats by activating PI3K/Akt pathway.