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奥氮平介导环磷酸腺苷反应元件结合蛋白/脑源性神经营养因子/酪氨酸蛋白激酶受体B通路对精神分裂模型大鼠的神经修复作用
姚素华 鄢骏 谢芳 林春华 黄争春
解剖学报 ›› 2023, Vol. 54 ›› Issue (6) : 660-667.
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PDF(5379 KB)
奥氮平介导环磷酸腺苷反应元件结合蛋白/脑源性神经营养因子/酪氨酸蛋白激酶受体B通路对精神分裂模型大鼠的神经修复作用
姚素华1* 鄢骏1 谢芳1 林春华2 黄争春3
Nerve repair effect of olanzapine-mediated cyclic AMP response element binding protein/brain-derived neurotrophic factor/receptor tyrosine kinase receptors B pathway on schizophrenic rats
目的 探讨奥氮平通过对环磷酸腺苷反应元件结合蛋白（CREB）/脑源性神经营养因子（BDNF）/酪氨酸蛋白激酶受体B（TrkB）通路的影响对精神分裂模型大鼠的神经修复作用。 方法 将60只大鼠纳入对照组、模型组、奥氮平低、中、高剂量组，各组均10只。模型组、奥氮平低、中、高剂量组大鼠进行MK-801腹腔注射 0.2 mg/(kg ·d)， 对照组注射等量生理盐水。模型建立成功24 h后，奥氮平低、中、高剂量组分别以0.5、1.0~1.5 mg/(kg ·d)奥氮平溶液灌胃，对照组、模型组同剂量生理盐水灌胃。按照共济失调和刻板行为标准对大鼠行为学进行评分；Morris水迷宫实验评定大鼠认知功能及学习能力；ELISA法检测大鼠血清肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）水平；观察海马组织病理学变化；检测海马区细胞凋亡及CREB/BDNF/TrkB通路相关蛋白表达。 结果 与对照组比较，模型组大鼠共济失调、刻板行为评分、TNF-α、IL-6表达、细胞凋亡率极显著增加（P<0.01），奥氮平低、中剂量组显著增加（P<0.05）。与对照组比较，模型组大鼠跨越平台次数、目标象限停留时间、CREB、磷酸化CREB（p-CREB）、磷酸化TrkB（p-TrkB）、TrkB、BDNF蛋白相对表达极显著减少（P<0.01），奥氮平低、中剂量组显著减少（P<0.05）。与模型组比较，奥氮平低、中剂量组跨越平台次数、目标象限停留时间显著增加（P<0.05），奥氮平高剂量组极显著增加（P<0.01）。模型组以及奥氮平低剂量组中海马细胞肿大明显、细胞核破碎分裂、固缩，组织排列杂乱；奥氮平中、高剂量组大鼠海马细胞中少见破碎分裂以及核固缩现象，整体组织与对照组大鼠相似。 结论 奥氮平对精神分裂症模型大鼠的神经修复作用机制涉及到改善大鼠认知功能受损、保护大鼠海马神经细胞以及激活CREB/BDNF/TrkB信号通路的表达。
Objective To study the nerve repair effect of olanzapine on schizophrenia model rats through its effect on cyclic AMP response element binding protein（CREB）/brain-derived neurotrophic factor（BDNF）/receptor tyrosine kinase receptors B（TrkB）pathway. Methods Total 60 rats were divided into control group, model group, olanzapine low, middle and high dose group. The rats in the model group, olanzapine low, middle and high dose groups were injected intraperitoneally with MK-801［0.2 mg/(kg ·d)］, while the control injected with the same amount of normal saline. The low, middle and high dose olanzapine groups were perfused with olanzapine solution of 0.5 mg/(kg ·d),1.0 mg/(kg ·d) and 1.5mg/(kg ·d) respectively. The behavior of rats was scored according to ataxia and stereotyped behavior standards, cognitive function and learning ability were evaluated by Morris water maze test, serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were detected by ELISA method, hippocampal histopathology was observed under microscope, and apoptosis and expression of CREB/BDNF/TrkB pathway related proteins in hippocampus were detected. Results Compared with the control group, the ataxia, the score of stereotyped behavior, the expression of TNF-α, IL-6 and the rate of apoptosis in the model group increased significantly (P<0.01). Compared with the control group, the number of crossing the platform, the time of staying in the target quadrant and the relative expression of CREB, p-CREB, p-TrkB, TrkB and BDNF protein in the model group decreased significantly (P<0.01), and those in the low and middle dose olanzapine groups decreased significantly (P<0.05). Compared with the model group, the times of crossing the platform and the stay time in the target quadrant increased significantly in the low and middle dose olanzapine groups (P<0.05). In the model group and the low dose olanzapine group, the hippocampal cells were swollen obviously, the nucleus was broken and divided, pyknosis, and the tissue arrangement was disorderly, while the phenomenon of fragmentation and nuclear pyknosis was rarely seen in the middle and high dose olanzapine groups. Conclusion The nerve repair mechanism of olanzapine on schizophrenic model rats is related to improving cognitive impairment, protecting hippocampal neurons and activating the expression of CREB/BDNF/TrkB signal pathway in rats.
奥氮平 / 环磷酸腺苷反应元件结合蛋白/脑源性神经营养因子/酪氨酸蛋白激酶受体B通路 / 精神分裂 / 神经修复 / 酶联免疫吸附测定 / 大鼠
Olanzapine / Cyclic AMP response element binding protein/brain-derived neurotrophic factor/receptor tyrosine kinase receptors B pathway / Schizophrenia / Nerve regeneration / Enzyme-linked immunosorbent assay / Rat
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