贺园园， 张慧灵^*

（  苏州大学药学院，苏州 215123；  ）

摘要： 目的：探索和研究丙戊酸钠（valproate, VPA）对缺血性脑中风诱导的胶质瘢痕的作用及其机制。方法：体内建立大鼠短暂性大脑中动脉阻塞(transient middle cerebral artery occlusion, tMCAO)模型，检测脑萎缩体积和神经行为学指标。体外建立原代培养新生大鼠皮层星形胶质细胞糖氧剥夺 (oxygen-glucose deprivation，OGD) 再复氧模型。乳酸脱氢酶(lactate dehydrogenase, LDH)检测VPA对OGD诱导的星形胶质细胞损伤的保护作用; Western Blotting检测VPA对胶质瘢痕标志性蛋白GFAP, neurocan, phosphacan表达的影响以及胶质瘢痕与乙酰化组蛋白H3,H4(acetyl-histone H3，H4)和Hsp70.1b的关系。结果：给予VPA能显著降低大鼠的脑萎缩体积，改善损伤后期的行为学症状(P<0.01)，降低星形胶质细胞的LDH漏出率(P<0.05, P<0.01)。Western Blotting结果显示给予1mM VPA后neurocan, phosphacan, GFAP表达均下调(P<0.05,P<0.01)，acetyl-histone H3,H4和Hsp70.1b表达显著上调。结论：VPA能够显著降低tMCAO再灌注模型大鼠脑萎缩体积，长期给予VPA对脑缺血大鼠后期的神经功能恢复有明显的改善作用；VPA对OGD和OGD再灌注诱导的星形胶质细胞损伤具有保护作用 ；VPA对缺血性脑中风诱导的胶质瘢痕具有抑制作用，这可能与其增加acetyl-histone H3，H4和Hsp70.1b表达有关。
关键词： 丙戊酸钠(VPA)；脑缺血；星形胶质细胞；胶质瘢痕

HE Yuanyuan， ZHANG Huiling^*

（  College of Pharmaceutical Sciences, Soochow University, Suzhou 215123；  ）

Abstract： Aim: To investigate the inhibitory effects and mechanisms of valproate (VPA) on ischemic stroke-induced glial scar formation. Methods: We established the model of transient middle cerebral artery occlusion (tMCAO) to detecte the volume of brain atrophy and the neurologic behavior. Oxygen-glucose deprivation (OGD) model was established to simulate the glial scar formation in vitro. Cell death was detected by a lactate dehydrogenase dectection kit. The changes in the expression of GFAP, neurocan, phosphacan, acetyl-histone H3, H4 and Hsp70.1b were detected by Western Blotting. Results: The results showed that intraperitoneal injection of VPA (250mg/kg/day) for one month could significantly reduce brain atrophy volume and improve behavioral deficits in rats models of MCAO-reperfusion (P<0.01). And also, In an OGD-reperfusion-induced glial scar formation model, VPA protected OGD-reperfusion-induced astrocytic cell death. In the meantime, VPA could reduce the levels of the glial scar markers GFAP, neurocan and phosphacan protein (P<0.05, P<0.01). Further investigation revealed that VPA up-regulated the protein levels of acetyl-histone H3, H4 and Hsp70.1b which was significantly reduced during glial scar formation (P<0.05, P<0.01). Conclusion: VPA can improve brain atrophy and behavioral deficits in the late stage of ischemic stroke rats and protect primary cultured astrocytes from OGD or OGD-reperfusion-induced injury, and the effects may be associated with the inhibition of glial scar formation via up-regulating the protein levels of acetyl-histone H3, H4 and Hsp70.1b.
Keywords： Valproate (VPA); Ischemic Stroke; Astrocytes; Glial Scar 

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