预防性应用辛伐他汀对大鼠脑出血后血肿体积和神经功能的影响

Effects of prophylactic application of simvastatin on hematoma volume and neurological function in rats with intracerebral hemorrhage

目的探讨预防性应用辛伐他汀对大鼠脑出血后血肿体积及神经功能的影响。方法将96只雄性成年SD大鼠随机分为对照组(n=24)、脑出血组(n=24)、高剂量辛伐他汀组(HS组,n=24)和低剂量辛伐他汀组(LS组,n=24)。采用Ⅶ型胶原酶注射法建立大鼠ICH模型,对照组注入1μl生理盐水。辛伐他汀干预组造模前2周给予辛伐他汀灌胃至造模当天(LS组2 mg/kg·d,HS组8 mg/kg·d)。造模前检测血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)水平;造模后24 h,每组取6只大鼠测定血肿体积;造模后5 d,每组取6只大鼠评估肢体运动功能,然后采用干/湿重法检测脑含水量;造模后5 d,每组取6只大鼠采用FluoroJade B染色检测血肿周围神经元变性;造模后5 d,每组取6只大鼠采用western blot检测血肿周围脑组织血管内皮生长因子(VEGF)、水通道蛋白(AQP)4、磷酸化胞外信号调节激酶(p-ERK)和磷酸化c-Jun氨基末端激酶(p-JNK)表达。结果与对照组相比,脑出血组血肿体积显著增加(P<0.05),脑含水量、血肿周围脑组织FJB阳性细胞数以及VEGF、AQP4、p-ERK和p-JNK表达水平均明显增高(P<0.05),神经功能显著变差(P<0.05)。预防性应用辛伐他汀,显著缩小血肿体积(P<0.05),显著降低脑含水量、血肿周围脑组织FJB阳性细胞数以及VEGF、AQP4、p-ERK和p-JNK表达水平(P<0.05),显著改善大鼠神经功能(P<0.05)。HS组血清TC和LDL-C水平、神经功能、血肿周围VEGF、AQP4、p-ERK和p-JNK表达水平较LS组显著改善(P<0.05),但两组血肿体积、脑含水量、血肿周围变性神经元数量均无统计学差异(P>0.05)。结论预防性应用辛伐他汀可能通过抑制VEGF和AQP4的表达,减轻血肿周围脑组织水肿,减少血肿周围神经元变性,从而改善大鼠脑出血后神经功能。

Objective To investigate the effects of prophylactic application of simvastatin on hematoma volume and neurologicalfunction in the rats with intracerebral hemorrhage （ICH）. Methods Ninety-six male SD rats were randomly divided into 4 groups of 24animals each, i.e., control, ICH, high dose simvastatin （HS） and low dose simvastatin （LS） groups. The rats received oral administration ofsimvastatin for 2 weeks before ICH was established in both the HS and LS groups. The serum lipid levels and hematoma volume weremeasured 24 hours after ICH. The neurological function and water content of brain tissues were determined 5 days after ICH in 6 rats ofeach group. The neuronal degeneration in 6 rats of each group and expression of vascular endothelial growth factor （VEGF）, aquaporin 4（AQP4）, phosphorylated exracellular signal regulated kinase （p-ERK） and phosphorylated c-Jun amino-terminal kinase （p-JNK） in theperihematomal tissues were determined by FluoroJade B （FJB） staining and western blot 5 days after ICH, respectively. Results Theserum lipid levels, water content of brain tissues and expression levels of VEGF, AQP4, p-ERK and p-JNK were significantly higher inthe ICH group than LS group （P〈0.01） which were significantly higher than HS group （P〈0.01）. The neurological function wassignificantly better in HS group than LS group （P〈0.05）, which was significantly better than ICH group （P〈0.05）. The number ofFJB-positive cells was significantly less in HS and LS groups than ICH group. There was no significant difference in the hematomavolume among ICH, HS and LS groups 24 hours after ICH （P〉0.05）. There was no significant difference in the number of FJB-positivecells between HS and LS groups （P〉0.05）. Conclusion Prophylactic application of simvastatin attenuates neurologic defect probably byup-regulating VEGF and AQP4 expressions in the perihematomal tissues and reducing perihematomal edema in rats with ICH.