辛伐他汀预先给药对大鼠脊髓缺血再灌注损伤的影响

Effects of simvastatin pretreatment on ischemia-reperfusion injury to spinal cord in rats

目的 评价辛伐他汀预先给药对大鼠脊髓缺血再灌注损伤的影响.方法 雄性SD大鼠96只,体重220～280 g,随机分为3组（n=32）：假手术组（S组）、缺血再灌注组（IR组）和辛伐他汀预先给药组（Si组）.IR组和Si组采用夹闭腹主动脉45 min后开放的方法制备脊髓缺血再灌注模型,Si组制备模型前3 d开始以辛伐他汀20 mg·kg-1·d-1灌胃,连续3 d.分别于再灌注6、12、24 h时取8只大鼠,进行后肢运动功能评分.分别于再灌注2、6、12、24 h时取8只大鼠,采集静脉血样,测定血清脑型肌酸激酶同工酶（CK-BB）活性.取完血样后取大鼠脊髓组织,测定Toll样受体4（TLR4）mRNA表达、NF-κB活性、TNF-α含量和细胞间粘附分子-1（ICAM-1）含量,光镜下观察脊髓的病理学结果.结果 与S组比较,IR组和Si组后肢运动功能评分降低,血清CK-BB活性、脊髓TLR4mRNA表达、NF-κB活性、TNF-α和ICAM-1含量升高（P＜0.05或0.01）.与IR组比较,Si组后肢运动功能评分升高,血清CK-BB活性、脊髓TLR4 mRNA表达、NF-κB活性、TNF-α和ICAM-1含量降低（P＜0.05或0.01）.Si组脊髓病理学损伤程度轻于IR组.结论 辛伐他汀预先给药可减轻大鼠脊髓缺血再灌注损伤,其机制与下调TLR4表达、抑制NF-κB激活,从而减轻炎性反应有关.

Objective To investigate the effects of simvastatin pretreatment on ischemia-reperfusion （I/R）injury to the spinal cord in rats. Methods Ninety-six healthy male SD rats weighing 220-280 g were randomly divided into 3 groups （n=32 each）： Ⅰ group sham operation （group S）; Ⅱ group I/R and Ⅲ group simvastatin pretreatment （group Si）. The animals were anesthetized with 10% chloral hydrate 0.4 ml/100g. I/R to the spinal cord was induced by cross-clamping the aorta below renal artery for 45 min followed by reperfusion according to Zivin in group Ⅱ and Ⅲ. In group Ⅲ simvastatin 20 mg/kg was administered via gastric tube in the morning for 3 days before operation. Neurological function was assessed and scored （0 = no spontaneous movement of the hindlimbs, 7 = normal gait） at 2, 6, 12 and 24 h （n = 8 at each time point）. The animals were then sacrificed and the lumbar segment （L2-5） of the spinal cord was removed for microscopic examination and determination of expression of TLR4 mRNA, NF-κB protein activity and TNF-α and ICAM-1 contents in the spinal cord. Results I/R to the spinal cord significantly increased TLR4 mRNA expression, NF-κB protein activity and TNF-α and ICAM-1 content in the spinal cord and decreased neurological scores in group Ⅱ compared with group C. Simvastatin pretreatment significantly attenuated the I/R-induced increase in the above-mentioned variables and ameliorated I/R-induced neurological dificit and histopathological damage. Conclusion Simvastatin pretreatment has neuroprotective effects on the spinal cord against I/R injury by attenuating inflammatory response.