Neuroprotective effects　of　poly(ADP-ribose) polymerase inhibitors in transient focal cerebral ischemia of rats

目的：研究多聚ＡＤＰ核糖多聚酶（ＰＡＲＰ）在局灶性脑缺血再灌注损伤中的作用．方法：雄性Ｗｉｓｔａｒ大鼠用插丝法阻塞大脑中动脉３５ｈ后再灌注，梗塞灶用ＴＴＣ染色显示，图象分析测量；神经功能缺损采用０－５级评分．结果：低剂量ＰＡＲＰ抑制剂３氨基苯甲酰胺（１０ｍｇ·ｋｇ－１）或尼克酰胺（２０ｍｇ·ｋｇ－１）具有明显的神经保护作用，治疗窗近６ｈ；高剂量反而加重脑损伤，特别是尼克酰胺在再灌注起始给药．选择性单ＡＤＰ核糖酰转移酶抑制剂对脑梗塞无明显作用．结论：暂时非完全性抑制ＰＡＲＰ对脑缺血再灌注损伤产生神经保护作用，然而完全抑制该酶（尤其是在再灌注期）则产生损害作用．

AIM: To explore the role of poly(ADP ribose) polymerase (PARP) in focal cerebral ischemia with reperfusion injury. METHODS: Male Wistar rats underwent 3 5 h of temporary middle cerebral artery occlusion by intraluminal suture. Infarction volume was showed with 2,3,5 triphenyltetrazolium chloride (TTC) staining and quantitated by image analysis system, neurologic scores were determined with a 0-5 grading scale. RESULTS: 3 Aminobenzamide (3 AB) 10 mg·kg -1 or nicotinamide (Nic) at 20 mg·kg -1 showed potent neuroprotective effects within 0-6 h, neurologic deficits were attenuated. With the increasing dose of PARP inhibitors, beneficial effects were compromised, particularly, administration of Nic 60 mg·kg -1 at the onset of reperfusion drastically accelerated brain damage. Phytomenadione, a selective inhibitor of mono(ADP ribosyl) transferase, had little effect on infarction volume. CONCLUSION: Transient incomplete inhibition of PARP provides a neuroprotective effects against cerebral ischemia reperfusion injury, with a relatively wide therapeutic window, whereas severe inhibition of this enzyme, especially in reperfusion phase, is detrimental.