Wide therapeutic time window for fasudil neuroprotection against ischemia-induced delayed neuronal death in gerbils
| Autor: | Shin'ichi Satoh, Toshio Asano, Ichiro Ikegaki, Yoshinori Toshima, Masakazu Iwasaki |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Time Factors Thromboxane Ischemia Pharmacology Gerbil Neuroprotection chemistry.chemical_compound 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Edaravone Medicine Ozagrel Animals Molecular Biology Neurons Cell Death Dose-Response Relationship Drug business.industry General Neuroscience Fasudil Free Radical Scavengers medicine.disease Free radical scavenger Neuroprotective Agents chemistry Anesthesia Neurology (clinical) business Gerbillinae Antipyrine Developmental Biology |
| Zdroj: | Brain research. 1128(1) |
| ISSN: | 0006-8993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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