环氧合酶-2抑制药塞来昔布对CCI模型大鼠疼痛及PI3K/AKT通路的影响

Effects of Cyclooxygenase-2 Inhibitor Celecoxib on Pain and PI3K/AKT Pathway in CCI Model Rats

目的:探讨环氧合酶-2(COX-2)抑制药塞来昔布对坐骨神经慢性结扎损伤(CCI)模型大鼠疼痛及正磷脂酰肌醇3-激酶(PI3K)/蛋白质丝氨酸苏氨酸激酶(AKT)通路的影响。方法:制备CCI大鼠模型,随机分为模型组、塞来昔布低(20 mg·kg^-1)、中(40 mg·kg^-1)、高(60 mg·kg^-1)剂量组、加巴喷丁(100 mg·kg^-1)组,每组12只;另取12只设为假手术组。以机械性疼痛刺激实验、热敏实验、神经传导速率实验分别检测各组大鼠缩爪阈值、热敏潜伏期、神经传导速度;以酶联免疫吸附实验(ELISA)试剂盒检测血清中白介素6(IL-6)、肿瘤坏死因子α(TNF-α)水平;免疫印迹实验检测脊髓组织中PI3K/AKT通路蛋白(PI3K、pPI3K、AKT、p-AKT)表达情况。结果:与假手术组比较,模型组大鼠缩爪阈值、热敏潜伏期、神经传导速度明显降低(P<0.05),IL-6及TNF-α水平、p-PI3K/PI3K、p-AKT/AKT明显增高(P<0.05);与模型组比较,塞来昔布低、中、高剂量组及加巴喷丁组大鼠缩爪阈值、热敏潜伏期、神经传导速度明显升高(P<0.05),IL-6及TNF-α水平、p-PI3K/PI3K、p-AKT/AKT明显降低(P<0.05),塞来昔布各组呈剂量依赖性(P<0.05);塞来昔布高剂量组与加巴喷丁组相比,差异无统计学意义(P>0.05)。结论:COX-2抑制药塞来昔布可降低CCI模型大鼠炎症反应,减轻疼痛,改善其临床症状,可能是通过下调PI3K/AKT通路实现的。

Objective:To investigate the effect of celecoxib,a cyclooxygenase-2(COX-2)inhibitor,on pain and PI3K/AKT pathway in rats with chronic construction injury(CCI)of sciatic nerve.Methods:CCI rat models were prepared and randomly divided into the model group,celecoxib(COX-2 inhibitor)low(20 mg·kg^-1),medium(40 mg·kg^-1)and high(60 mg·kg^-1)dose groups and gabapentin(100 mg·kg^-1)group with 12 rats in each group,and another 12 rats were used as the sham operation group.Mechanical pain stimulation test,thermal sensitivity test and nerve conduction rate test were used to detect the claw shrinkage threshold,thermal latency and nerve conduction velocity of rats in each group,the levels of IL-6 and TNF-αin serum were detected by ELISA kit,and the expressions of PI3K/AKT pathway proteins(PI3K,p-PI3K,AKT,p-AKT)in spinal cord tissue were detected by immunoblotting.Results:Compared with those in the sham operation group,the claw shrinkage threshold,thermal latency and nerve conduction velocity of rats in the model group were significantly lower(P<0.05),while the levels of IL-6 and TNF-α,p-PI3K/PI3K and p-AKT/AKT were significantly increased(P<0.05).Compared with those in the model group,the claw shrinkage threshold,thermal latency and nerve conduction velocity of rats in celecoxib low,medium and high dose groups and gabapentin group increased(P<0.05),while the levels of IL-6 and TNF-α,p-PI3K/PI3K and p-AKT/AKT were decreased(P<0.05),and there was a dose-dependent manner in celecoxib each groups(P<0.05).There were no significant differences between celecoxib high dose group and gabapentin group(P>0.05).Conclusion:Celecoxib,a COX-2 inhibitor,can reduce inflammation,alleviate pain and improve clinical symptoms in CCI model rats probably by down-regulating PI3K/AKT pathway.