诱生型一氧化氮合酶抑制剂对大鼠脑缺血再灌注损伤的保护作用

A study on the protective effects of iNOS inhibitor AG on focal cerebral ischemia reperfusion damage in rats

目的 探讨诱生型一氧化氮合酶抑制剂 (iNOSI)氨基胍 (aminoguanidine ,AG)对大鼠脑缺血 再灌注 (ischemia reperfusion ,IR)后期的保护作用。方法 采用Longa改良法 ,建立局灶缺血 再灌注模型。于再灌注即刻给予AG(10 0mg/kg ,每天两次 ) ,测定再灌注后不同时点 (6h ,12h ,2 4h ,48h ,72h ,7d)脑内NOS活性的动态变化及脑梗死体积 ,并对顶叶皮层半暗带区进行光镜下观察。结果 再灌注后 12h～ 72h ,AG治疗组NOS活性明显降低 ,梗死体积减小 ,光镜下病理学观察也表明 ,各时点AG治疗组顶叶皮层神经元变性数目及变性程度均减轻 ,微循环障碍也有不同程度缓解。结论 大鼠大脑中动脉闭塞 3h ,于再灌注即刻给予AG ,可使脑梗死体积缩少 ,使半暗带区神经元变性、微循环障碍程度减轻 ,起到对脑保护的作用。

Objective To investigate the protective effect of aminoguanidine (AG),an inhibitor of inducible NO synthase(iNOS),on focal cerebral ischemia reperfusion (IR) damage in rats.Methods In Wistar rats anesthetized with 6% chloral hydrate (5 ml/kg body weight,i.p.),the left middle cerebral artery was occluded by the thread according to the method described by Zea Longa et al.Three hours later,the thread was removed to allow reperfusion and intraperitoneal injection of AG (100 mg/kg twice per day) was given.The rats were randomly divided into 3 groups:(1)sham operated group,(2)vehicle control group,(3) AG treated group.The rats were sacrificed 6 h、12 h、24 h、48 h、72 h or 7 d after MCA occlusion and infarct volume was determined by image analysis in TTC stained brain sections.The activity of NOS was measured by colorimetry and the neuropathology was observed by light microscopy after hematoxylin eosin and Nissl staining.Results Administration of AG attenuated induced NOS activity by 18.29%,31.27%,18.39%,21.29% 12 h,24 h,48 h and 72 h after IR compared with vehicle control group(P<0.05).The differences were statistically significant.AG reduced infarct volume significantly in the comparison between the 24h and 7day groups.The abnormalities observed under light microscope were alleviated.Conclusions AG selectively inhibits iNOS activity and reduces the volume of the infarct produced by transient MCA occlusion.AG also have protective effect on penumbra area.The protective effect of AG is time dependent and occurs only when the drug is administered for longer than 12 hours,starting after induction of IR.