W1302对大鼠急性缺血性脑卒中模型脑保护作用研究  

The neuroprotective effect of W1302 on acute ischemic stroke in rats

作　　者：徐少锋[1] 李江[1] 蔡杰 冯楠[1] 张咪 王玲[1] 王伟平 黄海洪[1] 王琰[1] 王晓良[1] XU Shao-feng;LI Jiang;CAI Jie;FENG Nan;ZHANG Mi;WANG Ling;WANG Wei-ping;HUANG Hai-hong;WANG Yan;WANG Xiao-l iang(Institute of Material Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,北京100050

出　　处：《药学学报》2024年第9期2539-2544,共6页Acta Pharmaceutica Sinica

基　　金：新药作用机制研究与药效评价北京市重点实验室(BZ0150)。

摘　　要：硝酸2-(4-甲基噻唑-5-基)乙酯盐酸盐(W1302)是含硝基的氯美噻唑衍生物,它是一种既有一氧化碳(carbon monoxide, NO)供体又具有弱γ-氨基丁酸A型(γ-aminobutyric acid type A, GABA_(A))受体的变构调节激动作用的新型脑保护剂。当前研究采用大脑中动脉缺血再灌注(transient middle cerebral artery occlusion, tMCAO)脑损伤大鼠模型,评价W1302对缺血性脑卒中的治疗作用,并探索其潜在的作用机制。本实验经过中国医学科学院药物研究所实验动物管理和使用委员会的审查批准(伦理审查表号No. 620、632、5013)。研究结果显示:灌胃给予1、3、10 mg·kg^(-1)剂量的W1302,可显著减少缺血2 h再灌24 h大鼠脑梗死体积,且疗效优于200 mg·kg^(-1)丁基苯酞;显著增加血液和脑组织中NO水平,提高再灌后脑血流量和脑内三磷酸腺苷(adenosine triphosphate, ATP)含量;明显抑制脑组织炎症因子包括肿瘤坏死因子α (tumor necrosis factor-α, TNF-α)、白细胞介素-1β (interleukin-1β, IL-1β)的表达;抗脑缺血时间窗可达缺血后120~180 min。这些研究结果证明, W1302可通过增加NO释放,扩张血管、增加脑血流量,改善脑组织能量供应,升高ATP水平,抑制神经炎症,发挥其对tMCAO脑卒中模型大鼠的保护作用,从而为W1302治疗缺血性脑卒中的临床应用提供理论支持。2-(4-Methylthiazol-5-yl)ethyl nitrate hydrochloride(W1302)is a nitro containing derivative of clomethiazole,which is a novel neuroprotective agent with both carbon monoxide(NO)donor and weak y-aminobutyric acid type A(GABA_(A))receptor allosteric regulatory excitatory effect.The current study used a rat model of transient middle cerebral arteryocclusion(tMCAO)brain injury to evaluate the therapeutic effect of W1302 on ischemic stroke and explore its potential mechanisms of action.This experiment has been reviewed and approved by the Laboratory Animal Management and Use Committee of the Institute of Materia Medica,Chinese Academy of Medical Sciences(ethical review forms No.620,632,5013).The results showed that gavage administration of 1,3,and 10 mg·kg^(-1)of w1302 can significantly reduce the volume of cerebral infarction in rats with ischemia for 2 h and reperfusion for 24 h,and the therapeutic effect was better than that of 200 mg·kg^(-1) of DL-3n-butylphthalide.W1302 significantly increased NO levels in blood and brain tissue.It increased cerebral blood flow and brain adenosine triphosphate(ATP)content after reperfusion,as well as,inhibited the expressions of inflammatory factors tumor necrosis factor-α(TNF-a)and interleukin-1β(IL-1β)in brain tissue.The time window of W1302 was between 120-180 min after ischemia.These research results demonstrated that W1302 could increase NO release,dilate blood vessels,and increase cerebral blood flow,improve energy supply to brain tissue and increase ATP levels,and inhibit neuro-inflammation,which playing the protective roles in tMCAO stroke model rats.This provides theoretical support for the clinical application of W1302 in the treatment of ischemic stroke.

关 键 词：脑卒中 硝酸2-(4-甲基噻唑-5-基)乙酯盐酸盐 一氧化氮供体 GABA_(A)受体激动剂 神经炎症 

分 类 号：R966[医药卫生—药理学]