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J Zhejiang Univ (Med Sci)  2018, Vol. 47 Issue (1): 19-26    DOI: 10.3785/j.issn.1008-9292.2018.02.03
    
Effects of cysteinyl leukotrienes receptor antagonists on chronic brain injury after global cerebral ischemia/reperfusion
WANG Hao1(),GUO Honggang2,LOU Qi2,SHI Qiaojuan2,*()
1. Department of Neurology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
2. Laboratory Animal Center, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China
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Abstract  

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.



Key wordsLeukotriene antagonists/pharmacology      Cysteine      Albuterol/therapeutic use      Brain ischemia/physiopathology      Reperfusion injury/drug effects      Neurons/drug effects      Disease models, animal      Gerbillinae     
Received: 07 July 2017      Published: 12 June 2018
CLC:  R743  
  R96  
Corresponding Authors: SHI Qiaojuan     E-mail: wangh8234@163.com;shiqiaojuan@163.com
Cite this article:

WANG Hao,GUO Honggang,LOU Qi,SHI Qiaojuan. Effects of cysteinyl leukotrienes receptor antagonists on chronic brain injury after global cerebral ischemia/reperfusion. J Zhejiang Univ (Med Sci), 2018, 47(1): 19-26.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2018.02.03     OR     http://www.zjujournals.com/med/Y2018/V47/I1/19


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

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。


关键词: 白三烯拮抗剂/药理学,  半胱氨酸,  沙丁胺醇/治疗应用,  脑缺血/病理生理学,  再灌注损伤/药物作用,  神经元/药物作用,  疾病模型, 动物,  沙鼠亚科 
Fig 1 Diagram of regional cerebral blood flow during global cerebral ischemia and reperfusion in gerbils
Fig 2 Effects of Pranlukast and HAMI 3379 on neurological score and neurological function score 24 h, 14 d after global cerebral ischemia and reperfusion in gerbils
Fig 3 Pranlukast and HAMI 3379 inhibit the cerebral cortex neuron loss 14 d after global cerebral ischemia and reperfusion in gerbils(Nissl staining)
Fig 4 Pranlukast and HAMI 3379 inhibit the cerebral cortex microgila activation 14 d after global cerebral ischemia and reperfusion in gerbils(immunohistochemistry staining)
Fig 5 Pranlukast and HAMI 3379 inhibit the cerebral cortex astrocyte activation 14 d after global cerebral ischemia and reperfusion in gerbils(immunohistochemistry staining)
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