A newly synthesized poly(ADP-ribose) polymerase inhibitor, DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: pharmacological profiles, neuroprotective effects, and therapeutic time window in cerebral ischemia in rats.
We investigated the pharmacological profiles of DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one], a newly synthesized poly(ADP-ribose) polymerase (PARP) inhibitor, and its neuroprotective effects on ischemic injuries in vitro and in vivo. DR2313 competitively inhibited poly(ADP-ribosyl)ation in nuclear extracts of rat brain in vitro (K(i) = 0.23 microM). Among several NAD(+)-utilizing enzymes, DR2313 was specific for PARP but not selective between PARP-1 and PARP-2. DR2313 also showed excellent profiles in water solubility and rat brain penetrability. In in vitro models of cerebral ischemia, exposure to hydrogen peroxide or glutamate induced cell death with overactivation of PARP, and treatment with DR2313 reduced excessive formation of poly(ADP-ribose) and cell death. In both permanent and transient focal ischemia models in rats, pretreatment with DR2313 (10 mg/kg i.v. bolus and 10 mg/kg/h i.v. infusion for 6 h) significantly reduced the cortical infarct volume. To determine the therapeutic time window of neuroprotection by DR2313, the effect of post-treatment was examined in transient focal ischemia model and compared with that of a free radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolone-5-one). Pretreatment with MCI-186 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. infusion for 6 h) significantly reduced the infarct volume, whereas the post-treatment failed to show any effects. In contrast, post-treatment with DR2313 (same regimen) delaying for 2 h after ischemia still prevented the progression of infarction. These results indicate that DR2313 exerts neuroprotective effects via its potent PARP inhibition, even when the treatment is initiated after ischemia. Thus, a PARP inhibitor like DR2313 may be more useful in treating acute stroke than a free radical scavenger.
Nakajima
Hidemitsu
H
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Moro-oka-cho, Kohoku-ku, Yokohama 222-8567, Japan. hidemitsu_nakajima@meiji.co.jp
Kakui
Nobukazu
N
Ohkuma
Kunihiro
K
Ishikawa
Midori
M
Hasegawa
Toshifumi
T
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013379:Substrate Specificity; D013997:Time Factors
C497718:2-methyl-3,5,7,8-tetrahydrothiopyrano(4,3-d)pyrimidine-4-one; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011744:Pyrimidinones; D017382:Reactive Oxygen Species; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000077553:Edaravone; D000983:Antipyrine