QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.056572v1 307/3/961    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iwashita, A. Articles by Hisajima, H. Search for Related Content PubMed PubMed Citation Articles by Iwashita, A. Articles by Hisajima, H.

NEUROPHARMACOLOGY

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

Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan

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.

Address correspondence to: Akinori Iwashita, Department of Neuroscience, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. E-mail: aki_iwashita{at}po.fujisawa.co.jp

This article has been cited by other articles:

				A. Iwashita, Y. Muramatsu, T. Yamazaki, M. Muramoto, Y. Kita, S. Yamazaki, K. Mihara, A. Moriguchi, and N. Matsuoka Neuroprotective Efficacy of the Peroxisome Proliferator-Activated Receptor {delta}-Selective Agonists in Vitro and in Vivo J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1087 - 1096. [Abstract] [Full Text] [PDF]

				A. Iwashita, N. Tojo, S. Matsuura, S. Yamazaki, K. Kamijo, J. Ishida, H. Yamamoto, K. Hattori, N. Matsuoka, and S. Mutoh A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 425 - 436. [Abstract] [Full Text] [PDF]