辛伐他汀在弥漫性轴索损伤后神经保护中的作用及其机制

The role and mechanism of simvastatin in neuroprotection after diffuse axonal injury

目的探索辛伐他汀预处理在弥漫性轴索损伤(DAI)后神经保护中的作用,并初步阐明可能的机制。方法采用大鼠头颅瞬间旋转损伤装置制备大鼠DAI模型,模型制作前随机给予白开水或辛伐他汀[60mg/(kg·d)]灌胃1周,DAI后24h用改良神经功能缺损程度评分(mNSS)评估神经功能状态,处死并取脑,脑组织切片行HE染色、Mallory磷钨酸苏木素染色、淀粉样蛋白前体(APP)免疫组化染色及TUNEL染色,另外大鼠用于提取脑组织蛋白行RhoA活性检测。结果 DAI后大鼠都出现明显神经功能缺失,组织病理学可见神经元死亡,轴突断裂。辛伐他汀预处理后神经功能有明显改善,APP分数明显降低,TUNEL染色强度也有降低。RhoA活性检测结果显示DAI后RhoA活性升高,但此效应可被辛伐他汀抑制。相关性分析显示RhoA活性与APP分数及TUNEL结果都有显著相关性。实验前后大鼠的生理指标和血液生化指标无明显差异。结论辛伐他汀可改善DAI后神经功能状态,且此作用与抑制RhoA活性有关。

Objective To investigate the neuroprotective effects of simvastatin after diffuse axonal injury （DAI） to clarify its possible mechanism. Methods The model of DAI was established by instant head rotation in 32 adult rats. The rats were randomly divided into simvastatin group and plain water group, which were respectively given simvastatin E60 mg/（kg ~ d）] or plain water of the same volume via garage for a week. Then the two groups were subdivided into DAI group and sham group, with 8 in each group. Twenty-four hours after DAI attack, the rats were evaluated for the modified neurological severity score （mNSS）. After rats were killed, rat brain was harvested for HE staining, Mallory phosphotungstic acid hematoxylin staining （PTAH）, amyloid precursor protein （APP） immunohistochemistry and TUNEL staining. The other four brains in each group were harvested and brain- tissue proteins were extracted for RhoA activity analysis. Results There were an obvious neurological deficits in the rats after DAI. Histopathologic results showed neuronal death and axonal disruption. Simvastatin pretreatment could obviously improve the neurological function, decrease the APP score and reduce neuronal death. RhoA activity was increased after DAI, and the effect was significantly suppressed by simvastatin. Both APP score and the results TUNEL staining significantly correlated with RhoA activity. Physiological or biochemistry indicators did not change significantly before and after simvastatin treatment. Conclusion Simvastatin pretreatment can improve neurological function after DAI via suppressing RhoA activity.