半胱氨酰白三烯受体拮抗剂对全脑缺血再灌注慢性损伤的作用

摘要

Objective: To investigate the effects of cysteinyl leukotrienes receptor ( CysLTR ) antagonists on global cerebral ischemia/reperfusion ( CI/R ) injury in gerbils, and to explore its mechanism. Methods:Totally 40 gerbils weighting 45-65 g were randomized into sham, saline, Pranlukast and HAMI 3379 groups with 10 animals in each. The CI/R model was established in gerbils by bilateral common carotid occlusion for 10 min followed by reperfusion. After ischemia, the CysLTR antagonists Pranlukast (0. 1 mg/kg) and HAMI 3379 (0. 1 mg/kg) were injected intraperitoneally for 5 consecutive days in the last two groups,while the former two groups were injected with saline only (10 mL/kg) . After 24 h or 14 d reperfusion, neurological deficit score was evaluated and the behavioral dysfunction was assessed, respectively. And 14 d after reperfusion, the neuron morphology of cerebral cortex was observed in brain sections stained with Cresyl violet. In addition, the Iba-1 ( microgila ) and GFAP ( astrocyte ) positive cells in cerebral cortex were observed by using immunohistochemitry method. Results:CI/R models were successfully established in 21 out of 30 gerbils with 7 in saline group, 6 in Pranlukast group, and 8 in HAMI 3379 group. Compared with saline group, Pranlukast and HAMI 3379 significantly attenuated neurological deficits, improved the behavioral function 24 h after reperfusion(all P<0. 01); Pranlukast and HAMI 3379 also significantly improved the behavioral function 14 days after reperfusion (P<0. 05 or P<0. 01). Compared with saline group, the neurological symptom scores in Pranlukast and HAMI 3379 groups presented a trend of amelioration 14 d after reperfusion, but it was not significant(P>0. 05). In addition, Pranlukast and HAMI 3379 also inhibited the neuron loss and injury, suppressed microgila and astrocyte activation 14 d after reperfusion ( all P <0 . 01 ) . Conclusion: CysLTR antagonists Pranlukast and HAMI 3379 have long-term neuroprotective effect on chronic brain injury induced by global cerebral ischemia/reperfusion in gerbils.%目的:研究半胱氨酰白三烯受体(CysLTR)拮抗剂普鲁司特和HAMI 3379对全脑缺血再灌注慢性损伤的保护作用及相关作用机制.方法:40只体质量为45～65 g的清洁级健康雄性长爪沙鼠分为手术对照组、模型对照组、普鲁司特组和HAMI 3379组,每组10只.采用结扎双侧颈总动脉10 min再灌注法制作全脑缺血再灌注损伤模型.普鲁司特组和HAMI 3379组于术前30 min和术后30 min、4 h、12 h分别腹腔注射普鲁司特和HAMI 3379,第二天起每天分别给药一次,连续给药5 d.于全脑缺血再灌注24 h和14 d时对各组的神经症状和功能进行评分;尼氏染色法观察再灌注14 d时各组大脑皮层神经元的形态和数量;免疫组织化学染色检测再灌注14 d时各组大脑皮层小胶质细胞和星形胶质细胞激活情况.结果:30只长爪沙鼠中,21只造模成功,其中模型对照组7只,普鲁司特组6只,HAMI 3378组8只.与模型对照组比较,普鲁司特组和HAMI 3379组术后24 h神经症状评分降低(均P<0.01),术后14 d普鲁司特组和HAMI 3379组的神经症状评分较模型对照组亦有改善的趋势,但差异均无统计学意义(均P>0.05);普鲁司特组和HAMI 3379组在这两个时间点的神经功能评分均高于模型对照组(P<0.05或P<0.01).普鲁司特组和HAMI 3379组大脑皮层神经元损伤较模型对照组减轻,存活神经元密度与模型对照组差异有统计学意义(均P<0.01).普鲁司特组和HAMI 3379组大脑皮层小胶质细胞和星形胶质细胞增生情况较模型对照组改善(均P<0.01).结论:普鲁司特和HAMI 3379对长爪沙鼠全脑缺血慢性损伤模型具有较持久的神经保护作用.