PJ34对脑缺血再灌注大鼠应用rt-PA后血脑屏障完整性的影响

Effect of PJ34 on blood-brain barrier integrity after injecting of rt-PA in rats with cerebral ischemia-reperfusion

目的研究多聚ADP核糖聚合酶-1(poly-ADP ribose polymerase-1,PARP-1)抑制剂PJ34能否改善脑缺血再灌注大鼠应用重组人组织型纤溶酶原激活物(recombinant tissue plasminogen activator,rtPA)后的血脑屏障完整性。方法将60只大鼠随机分为假手术组、缺血再灌注(ischemia-reperfusion,IR)组、rt-PA组及PJ34组。IR组:采用改良Zea Longa线栓法,制备局灶性脑缺血2 h再灌注模型。PJ34组及rt-PA组:缺血2 h拔出鱼线,同时给予尾静脉注射rt-PA 10 mg/kg,腹腔注射PJ34或生理盐水3 mg/kg。进行神经功能缺损评分、伊文氏蓝测定血脑屏障通透性、免疫组化分析MMP-9、Claudin-5、ZO-1的表达。结果 rt-PA组的神经功能缺损评分、伊文氏蓝含量及MMP-9表达均高于IR组,PJ34组低于rt-PA组,但高于IR组(P<0.05);rt-PA组的Claudin-5、ZO-1表达低于IR组,PJ34组高于rt-PA组,但低于IR组(P<0.05)。结论 PJ34通过抑制MMP-9的表达,增加Claudin-5、ZO-1的表达,可以有效改善脑缺血再灌注后应用rt-PA的大鼠血脑屏障完整性。

Objective To investigate whether the poly-ADP ribose polymerase-1(PARP-1)inhibitor PJ34,N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-dimethylamino can improve the integrity of the blood-brain barrier after rt-PA administration in rats with cerebral ischemia reperfusion.Methods Totally 60 rats were randomly divided into a sham operation group,an IR group,a rt-PA group and a PJ34 group.IR group:focal cerebral ischemia 2 h reperfusion model was made by modifying Zea Longa method.PJ34 group and rt-PA group:the fish line was removed 2 h after ischemia,rt-PA(10 mg/kg)was administered to the tail vein,and PJ34 or physiological saline(3 mg/kg)was intraperitoneally injected.The neurological function score was evaluated,the permeability of the blood-brain barrier was measured by Evans blue staining,and the expressions of MMP-9,Claudin-5 and ZO-1 was analyzed by immunohistochemistry.Results The mNSS score,Evans blue content and MMP-9 expression in rt-PA group were significantly higher than those in the IR group,and those in PJ34 group were lower than those in rt-PA group,but were higher than those in IR group(P<0.05).The expression of Claudin-5 and ZO-1 in rt-PA group was lower than that in IR group,higher in PJ34 group than in rt-PA group,but lower than that in IR group(P<0.05).Conclusions PJ34 can effectively improve the integrity of blood-brain barrier of rt-PA rats after cerebral ischemia by inhibiting the expression of MMP-9 and increasing the expressions of Claudin-5 and ZO-1.