title: Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia.
abstract: Cerebral ischemia induces excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), leading to neuronal cell death and the development of post-ischemic dysfunction. Blockade of PARP-related signals during cerebral ischemia has become a focus of interest as a new therapeutic approach for acute stroke treatment. The purpose of the present study was to examine the pharmacological profiles of MP-124, a novel water-soluble PARP-1 inhibitor, and its neuroprotective effects on ischemic injury in vitro and in vivo. MP-124 demonstrated competitive inhibition of the PARP-1 activity of human recombinant PARP-1 enzyme (Ki=16.5nmol/L). In P388D(1) cells, MP-124 inhibited the LDH leakage induced by H(2)O(2) in a concentration-dependent manner. (IC(50)=20.8nmol/L). In rat primary cortical neurons, MP-124 also inhibited the NAD depletion and polymerized ADP-ribose formation induced by H(2)O(2) exposure. Moreover, we investigated the neuroprotective effects of MP-124 in rat permanent and transient stroke models. In the rat permanent middle cerebral artery occlusion (MCAO) model, MP-124 was administered intravenously for 24h from 5min after the onset of MCAO. MP-124 (1, 3 and 10mg/kg/h) significantly inhibited the cerebral infarction in a dose-dependent manner (18, 42 and 48%). In rat transient MCAO model, MP-124 was administered intravenously from 30min after the onset of MCAO. MP-124 (3 and 10mg/kg/h) significantly reduced the infarct volume (53% and 50%). The present findings suggest that MP-124 acts as a potent neuroprotective agent in focal ischemia and its actions can be attributed to a reduction in NAD depletion and PAR formation.
authors.affiliation: Department II, Central Nervous System, Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Egi.Yasuhiro@mh.mt-pharma.co.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Egi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsuura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujio
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yuki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Akira
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; C560412:MP 124; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors