title: DY-9760e, a novel calmodulin antagonist, reduces infarction after permanent focal cerebral ischemia in rats.
abstract: DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate), a novel calmodulin antagonist, provides effective protection against Ca(2+) ionophore-induced cytotoxicity and brain injury induced by transient focal ischemia. In this study, we evaluated the effect of DY-9760e on ischemic infarct volume in rats subjected to permanent focal ischemia. DY-9760e (0.5 mg/kg/h for 6 h) significantly reduced the infarct volume when administered immediately after middle cerebral artery occlusion. Furthermore, this neuroprotection was also exerted by treatment with a 3-hour delay, implying that the therapeutic time window for this compound is at least 3 h. In addition, although treatment with 0.1 mg/kg/h for 24 h was ineffective, the combination of a loading dose of 0.3 mg/kg/h for 2 h followed by 0.1 mg/kg/h for 22 h yielded a significant reduction in infarct volume. Thus, prolonged infusion preceded by a loading dose is an efficacious dosing regimen for DY-9760e, especially at a low infusion rate. These data demonstrate the substantial neuroprotective effect of DY-9760e in a permanent focal ischemia model and indicate that this neuroprotectant may be of therapeutic value for the treatment of acute stroke.
authors.affiliation: New Product Research Laboratories II, Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sato
authors.forename: Hideo
authors.initials: H
authors.lastname: Takamori
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Shirasaki
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007191:Indazoles / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D007262:Infusions, Intravenous; D007564:Japan; D008297:Male; D020768:Middle Cerebral Artery / Q000601:surgery; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D020127:Recovery of Function; D013997:Time Factors
chemical_list: C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D002147:Calmodulin; D007191:Indazoles; D018696:Neuroprotective Agents