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

本研究的目的是确定是否选择性PARP（聚（ADP-核糖）聚合酶）抑制剂，KCL-440，将防止短暂局灶性脑缺血后的神经细胞死亡。使用管腔内缝合技术使Sprague-Dawley大鼠经受MCAo（Nito C等人，Brain Res 1008：179- 185，2004）2小时。将大鼠再灌注24小时并断头进行梗塞和水肿分析，选择性PARP抑制剂（KCL-440）治疗的动物在缺血发作后接受KCL-440（3.0或10.0 mg/kg）连续注射6小时，而溶剂治疗组接受相同剂量的溶剂。依达拉奉给药动物在再循环开始后即刻和30分钟后接受依达拉奉3.0 mg/kg剂量两次注射。在缺血期间，监测给药动物的颞肌和直肠温度，并将其维持在37℃。将动物随机分为以下四组（每组，n=10）：（I）赋形剂治疗组（对照组，n=10）， ...更多信息 （l）;（II）低剂量KCL-440治疗组（3.0 mg/kg）;（III）高剂量KCL-440治疗组（10.0 mg/kg）;（IV）依达拉奉治疗组（3.0 mg/kg × 2）。缺血期间，颞肌和直肠温度保持在37±0.2℃。低剂量KCL-440（II）可明显改善皮层和纹状体缺血性损伤（P<0.05）。此外，与I组和II组相比，高剂量KCL-440（III）显着减少皮质和纹状体梗死体积（p<0.05），并呈剂量依赖性。此外，与对照组（I）和依达拉奉给药组（IV）相比，KCl-440（II，III）还显著降低了皮质和纹状体水肿体积。这些结果表明，选择性PARP（聚（ADP-核糖）聚合酶）抑制剂，KCL-440具有较强的神经保护作用相比，依达拉奉已在日本临床应用，这种药物可能是一种新的治疗急性脑卒中的神经保护剂在临床领域。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