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

• Project/Area Number: 15590912
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nippon Medical School
• Principal Investigator: KAMIYA Tatsushi Nippon Medical School, Second Department of Internal Medicine, Assistant Professor, 医学部, 講師 (70233955)
• Co-Investigator(Kenkyū-buntansha): KATAYAMA Yasuo Nippon Medical School, Second Department of Internal Medicine, Professor and Chairmann, 医学部, 教授 (70152692)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: PARP / Rat / Focal Ischemia / Apoptosis / Neuronal cell death / Immunocytochemistry / In situ hybridization

Research Abstract

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 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.