title: A novel potent radical scavenger, 8-(4-fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine (FR210575), prevents neuronal cell death in cultured primary neurons and attenuates brain injury after focal ischemia in rats.
abstract: Reactive oxygen species (ROS) play a vital role in brain damage after cerebral ischemia-reperfusion injury, and ROS scavengers have been shown to exert neuroprotective effects against ischemic brain injury. We have recently identified 8-(4-fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (FR210575) as a novel, powerful free-radical scavenger. In the present study, the neuroprotective efficacy of FR210575 was evaluated in two neuronal death models in vitro as well as rat focal cerebral ischemia models in vivo. In the first model, primary cortical cultures were exposed to a high oxygen atmosphere (50% O2) for 48 h to induce cell death with apoptotic features. Treatment with FR210575 (10-7-10-5 M) significantly inhibited neuronal death. The second model used a growth-factor withdrawal paradigm. Withdrawal of TIP (transferrin, insulin, putrescine and progesterone)-supplemented medium induced apoptotic cell death after 2 days, but treatment with FR210575 exhibited dramatic protection against neuronal death. In two models of cerebral ischemia [photothrombotic occlusion of middle cerebral artery (MCA) for transient model and by permanent MCA occlusion for permanent model], rats received 3-h intravenous infusion (1-10 mg/kg/3 h) of FR210575, with brain damage determined 24 h later. FR210575 (3.2 mg/kg/3 h) significantly reduced the volume of focal damage in the cortex by 36% in the transient model and also reduced the size of ischemic brain damage in the permanent model. These findings indicate that the powerful radical scavenger FR210575 has potent neuroprotective activity and that FR210575 could be an attractive candidate for the treatment of stroke or other neurodegenerative disorders.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. aki_iwashita@po.fujisawa.co.jp
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwashita
authors.forename: Takuya
authors.initials: T
authors.lastname: Maemoto
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nakada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shima
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hisajima
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents; D010100:Oxygen / Q000494:pharmacology; D010777:Photochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C480781:8-(4-fluorophenyl)-2-(3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine; D000975:Antioxidants; D002934:Cinnamates; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D014227:Triazines; D010100:Oxygen