COX-2/NLRP3/IL-18信号通路在尼罗替尼对癫痫大鼠神经保护中的作用  

Role of COX-2/NLRP3/IL-18 signaling pathway in neuroprotective effect of nilotinib on epilepsy rats

作　　者：罗勇 毕文欢 袁威峰 LUO Yong;BI Wenhuan;YUAN Weifeng(Department of Neurology,The Second Affiliated Hospital of Shaoyang University,Shaoyang 422000,China)

机构地区：[1]邵阳学院附属第二医院神经内科一区,湖南邵阳422000

出　　处：《山东医药》2022年第16期44-47,共4页Shandong Medical Journal

摘　　要：目的探讨尼罗替尼对癫痫大鼠神经保护的机制及COX-2/NLRP3/IL-18信号通路的作用。方法采用戊四唑(PTZ)腹腔注射法诱导制作癫痫模型大鼠48只,将其随机分为模型组、SC-58125(即COX-2抑制剂)组、尼罗替尼组、尼罗替尼+SC-58125组,每组12只;另取12只正常大鼠为对照组。SC-58125组每天给予10 mg/kg的SC-58125灌胃,尼罗替尼组每天给予25 mg/kg尼罗替尼灌胃,尼罗替尼+SC-58125组每天给予25 mg/kg尼罗替尼和10 mg/kg SC-58125灌胃,对照组和模型组给予等量溶剂灌胃,每天1次,连续4周。末次给药1 h后,除对照组外,其余各组再次腹腔注射PTZ,观察大鼠癫痫发作情况,记录最终癫痫发作评分、癫痫发作潜伏期及持续时间。然后每组随机选取6只大鼠,断头取脑,分离海马组织,进行苏木精-伊红染色观察海马组织病理学变化,Western blotting法检测海马组织COX-2/NLRP3/IL-18通路相关蛋白表达。结果对照组无癫痫发作,癫痫模型大鼠最后一次注射PTZ后表现出明显的癫痫发作症状,可见海马CA1区神经元损伤。与模型组相比,SC-58125组和尼罗替尼组癫痫最终发作评分降低和癫痫发作持续时间缩短、发作潜伏期显著延长、海马CA1区神经元损伤减轻(P均<0.05)。与对照组相比,模型组海马组织COX-2、NLRP3、Cleaved Caspase-1和IL-1β、IL-18蛋白表达升高(P均<0.05);与模型组相比,SC-58125组和尼罗替尼组COX-2、NLRP3、Cleaved Caspase-1和IL-1β、IL-18蛋白表达降低(P均<0.05);尼罗替尼+SC-58125组COX-2、NLRP3、Cleaved Caspase-1和IL-1β、IL-18蛋白表达低于SC-58125组和尼罗替尼组(P均<0.05)。结论尼罗替尼可能通过抑制COX-2/NLRP3/IL-18信号通路降低PTZ诱导大鼠癫痫发作和海马神经元损伤。Objective To investigate the neuroprotective mechanism of nilotinib in epileptic rats and the effect of COX-2/NLRP3/IL-18 signaling pathway.Methods Forty-eight rat epilepsy models were successfully established by intraperitoneal injection of pentylenetetrazole(PTZ)and then were randomly divided into the model group,SC-58125(COX-2 inhibitor)group,nilotinib group,and nilotinib+SC-58125 group,with 12 in each group;another 12 normal rats were taken as the control group.The rats in the SC-58125 group were given 10 mg/kg SC-58125 by gavage every day,the rats in the nilotinib group were given 25 mg/kg nilotinib by gavage every day,and the rats in the nilotinib+SC-58125 group were given 25 mg/kg nilotinib and 10 mg/kg SC-58125 by gavage every day,and the rats in the control group and model group were given the same amount of solvent by gavage,once a day,for 4 consecutive weeks.One hour after the last administration,except for the control group,rats in the other groups were injected with PTZ again to observe the seizures of the rats,and the final seizure level,seizure latency and duration were recorded.Then,6 rats were randomly selected from each group,the brains were collected through decapitation,and the hippocampal tissues were isolated.HE staining was used to observe the histopathological changes of hippocampus,and Western blotting was used to detect the expression of COX-2/NLRP3/IL-18 pathway-related proteins in hippocampus.Results The rats in the control group had no seizures;the rats in the model group showed obvious seizures after the last injection of PTZ,and neuronal damage in hippocampal CA1 area was seen.Compared with the model group,the final seizure score decreased and the seizure duration of the rats in the SC-58125 group and the nilotinib group was shorter,the seizure latency was significantly prolonged,and the neuronal damage in the hippocampal CA1 area was alleviated(all P<0.05).Compared with the control group,the expression levels of COX-2,NLRP3,Cleaved Caspase-1,IL-1β,and IL-18 in the hippocampus of t

关 键 词：癫痫 尼罗替尼 神经炎症 戊四唑 环氧合酶2 NOD样受体蛋白3 白细胞介素18 大鼠 

分 类 号：R742.1[医药卫生—神经病学与精神病学]