Research on the Mechanism of PARP(Poly (ADP-ribose) polymerase) on neuronal cell death

本研究的目的是确定选择性PARP(聚(ADP-核糖)聚合酶)抑制剂KCL-440是否能预防大鼠局灶性短暂性脑缺血后的神经细胞死亡。采用腔内缝合技术(Nito C等，Brain Res 1008：179-185,2004)制作大鼠大脑中动脉闭塞模型，持续2小时。再灌流24小时后断头进行脑梗塞和水肿分析，选择性PARP抑制剂(KCL-440)处理组动物在缺血后连续注射KCL-440(3.0或10.0 mg/kg)6h，而赋形剂治疗组给予相同剂量的赋形剂。依达拉奉治疗组动物在再循环开始后和30min后两次注射依达拉奉3.0 mg/kg。在缺血期间，治疗动物的颞肌和直肠温度被监测并维持在37℃。动物随机分为4组(每组10只)：(1)赋形剂对照组(…(3)高剂量组(10 mg/kg)；(4)依达拉奉组(3.0 mg/kg×2)。缺血时，颞肌和直肠温度维持在37±0.2℃。与对照组(I)相比，小剂量KCL-440(II)可明显改善皮质和纹状体的缺血性损伤(P&lt；0.05)。此外，高剂量KCL-440(III)与I组和II组(P&lt；0.05)相比，显著缩小皮质和纹状体梗死体积(p&lt；0.05)。此外，与对照组(I)和依达拉奉治疗组(IV)相比，KCL-440(II，III)还能显著减少皮质和纹状体的水肿体积。提示选择性PARP(聚(ADP-核糖)聚合酶)抑制剂KCL-440与日本已在临床应用的依达拉奉相比，具有较强的神经保护作用，有望成为临床上治疗急性卒中的一种新的治疗神经保护剂。较少

The aim of this study is to determine whether a selective PARP(Poly (ADP-ribose) polymerase) inhibitor, KCL-440,would prevent neuronal cell death following transient focal ischemia in rats. Sprague-Dawley rats were subjected to MCAo using an intraluminal suture technique (Nito C et al., Brain Res 1008:179-185,2004) for 2hrs. The rats were reperfused for 24hrs and decapitated for infarct and edema analysis, a selective PARP inhibitor (KCL-440)-treated animals received a continuous injection of KCL-440(3.0 or 10.0 mg/kg) for 6 hrs by after the onset of ischemia, while vehicle-treated groups received same dose of vehicle. Edaravone-treated animals received a twice injection of edaravone at the dose of 3.0 mg/kg just after the onset of recirculation and 30 min after. During ischemia, temporal muscle and rectal temperatures were monitored and maintained at 37℃ in the treated animals. Animals were randomly divided into the following four groups (each, n=10) : (I)vehicle-treated group (contro … More l) ; (II)low dose KCL-440-treated group (3.0 mg/kg) ; (III)high dose KCL-440-treated group (10.0 mg/kg) ; (IV) edaravone-treated group (3.0 mg/kg x 2). Temporal muscle and rectal temperatures were maintained during ischemia at 37±0.2℃. Low dose KCL-440 (II)ameliorated the cortical and striatal ischemic damage compared with the control (I)significantly (p<0.05). Moreover, high dose KCL-440 (III) decreased the cortical and striatal infarct volume significantly compared with those of groups I and II (p<0.05) dose-dependently. Furthermore, KCL-440(II, III) also decreased the cortical and striatal edema volume significantly compared with those of control (I)and edaravone-treated group (IV). These results suggest that a selective PARP(Poly (ADP-ribose) polymerase) inhibitor, KCL-440 has a strong neuroprotective effect compared with edaravone that has already been applied clinically in Japan, and that this drug may be a new therapeutic neuroprotective agent for the treatment of acute stroke in clinical field. Less