Wide Therapeutic Time Window for Fasudil Neuroprotection Against Ischemia-induced Delayed Neuronal Death in Gerbils.
From: Research Center, Asahi Kasei Pharma Corporation 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan. sato.sn@om.asahi-kasei.co.jp
Brain research
- Publish Date: Jan 2007
- ISSN: 0006-8993
- Volume: 1128
- Issue: 1
- Pages: 175-80
- Medium: Print
- Language: English
- Citation (JAMA): Satoh Shin-ichi, Toshima Yoshinori, Ikegaki Ichiro, et al. Wide Therapeutic Time Window for Fasudil Neuroprotection Against Ischemia-induced Delayed Neuronal Death in Gerbils.. Brain Res. Jan 2007;1128:175-80
Abstract
The neuroprotective potential and therapeutic time window for fasudil, a Rho-kinase inhibitor (RKI), were evaluated for delayed neuronal death in gerbils. A preliminary screening was done on fasudil, ozagrel, and edaravone using a single administration in a delayed neuronal death study. Intraperitoneal (i.p.) administration of edaravone, a free radical scavenger (3, 10 mg/kg) immediately after re-circulation did not reduce neuronal degeneration. We previously reported that ozagrel, a thromboxane A(2) synthetase inhibitor (30 mg/kg) also did not reduce neuronal degeneration, while fasudil (3, 30 mg/kg) significantly protected against the ischemia-induced neuronal loss. To clarify the therapeutic time window of fasudil, which showed a positive effect in a preliminary screening, animals received their first i.p. administration of fasudil (10 mg/kg) 24 or 48 h after ischemia. Administration of fasudil twice daily was continued until day 6. Fasudil significantly protected against the ischemia-induced delayed neuronal death when the treatment was started 24 h after ischemia. In gerbils, hydroxyfasudil, an active metabolite of fasudil, was found following an i.p. administration of fasudil (10 mg/kg), and the value of the area under the plasma level curve of hydroxyfasudil was 7 times higher than that of fasudil. Hydroxyfasudil may contribute to the potency of fasudil. The present findings indicate that the RKI fasudil reduces ischemic neuronal damage with a wide therapeutic time window in gerbil, and may be useful in the treatment of acute ischemic stroke in humans.
Mesh Headings (Keywords): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Animals, Antipyrine, Cell Death, Dose-Response Relationship, Drug, Free Radical Scavengers, Gerbillinae, Ischemia, Male, Neurons, Neuroprotective Agents, Time Factors
Check for Full Text / PubMed Unique Identifier (PMID): 17123488
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