Neuroprotective effects of ONO-1924H, an inhibitor of poly ADP-ribose polymerase (PARP), on cytotoxicity of PC12 cells and ischemic cerebral damage.
N-[3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)phenyl]-4-(morpholin-4-yl) butanamide methanesulfonate monohydrate (ONO-1924H) is a novel inhibitor of poly ADP-ribose polymerase (PARP). In this study, we examined the effects of ONO-1924H on cytotoxicity induced by hydrogen peroxide in PC12 cells in vitro and cerebral damage and neurological deficits induced by middle cerebral artery (MCA) thrombus occlusion in vivo in rat. In the in vitro cytotoxicity assay, exposure to 0.5 mmol/L hydrogen peroxide induced cell death in differentiated PC12 cells. ONO-1924H, a PARP inhibitor (Ki=0.21 micromol/L), reduced cell death in a concentration-dependent manner that was correlated with inhibition of PARP activation. A 50% reduction in cell death (EC50) was achieved with 2.4 micromol/L ONO-1924H. In the MCA occlusion model, ONO-1924H was injected intravenously at doses of 3, 10 and 30 mg/kg/h for 3 h, and cerebral damage and neurological deficits were estimated 24 h after MCA occlusion. ONO-1924H treatment led to a significant decrease in cerebral damage in the 10 mg/kg/h-treated group (P < 0.05) and the 30 mg/kg/h-treated group (P < 0.01). Further, ONO-1924H at doses of 30 mg/kg/h significantly (P < 0.05) improved neurological deficits. These findings suggest that the novel PARP inhibitor, ONO-1924H, affords effective neuroprotection and is a useful therapeutic candidate for the treatment of ischemic stroke.
Kamanaka
Yoshihisa
Y
Minase Research Institute, ONO Pharmaceutical Co. Ltd., 3-1-1, Sakurai,Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
Kondo
Kazunao
K
Ikeda
Yasuhiko
Y
Kamoshima
Wataru
W
Kitajima
Takashi
T
Suzuki
Yasuhiro
Y
Nakamura
Yoichi
Y
Umemura
Kazuo
K
D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D006861:Hydrogen Peroxide / Q000633:toxicity; D007262:Infusions, Intravenous; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D009025:Morpholines; C493991:N-(3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)phenyl)-4-(morpholin-4-yl) butanamide methanesulfonate monohydrate; D018696:Neuroprotective Agents; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D006861:Hydrogen Peroxide