Wide therapeutic time window for Rho-kinase inhibition therapy in ischemic brain damage in a rat cerebral thrombosis model.
The aim of this study was to investigate the influence of delayed Rho-kinase inhibition with fasudil on second ischemic injury in a rat cerebral thrombosis model. Cerebral ischemia was induced in rats by injecting 150 mug of sodium laurate into the left internal carotid artery on day 1. In the ischemic group, the regional cerebral blood flow (rCBF) was significantly decreased 6.5 h after the injection. Fasudil (3 mg/kg/30 min i.v. infusion) significantly increased rCBF. The viscosity of whole blood was significantly increased 48 h after the injection of sodium laurate. Fasudil (10 mg/kg, i.p.) significantly decreased blood viscosity. To clarify the therapeutic time window of fasudil, rats received their first i.p. administration of fasudil (10 mg/kg) 6 h after an injection of sodium laurate. Administration of fasudil twice daily was continued until day 4. Fasudil prevented the accumulation of neutrophils within the brain as seen from measurements taken on day 3, and improved neuronal functions and reduced the infarction area as seen on day 5. Fasudil and hydroxyfasudil, an active metabolite of fasudil, concentration-dependently inhibited phosphorylation of myosin binding subunit of myosin phosphatase in neutrophils. The present results indicate that inhibition of Rho-kinase activation with fasudil is effective for the treatment of ischemic brain damage with a wide therapeutic time window by improving hemodynamic function and preventing the inflammatory responses. These results suggest that fasudil will be a novel and efficacious approach for the treatment of acute ischemic stroke.
Satoh
Shin-ichi
S
Research Center, Asahi Kasei Pharma Corporation 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan. sato.sn@om.asahi-kasei.co.jp
Toshima
Yoshinori
Y
Hitomi
Asako
A
Ikegaki
Ichiro
I
Seto
Minoru
M
Asano
Toshio
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives; D001783:Blood Flow Velocity / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020767:Intracranial Thrombosis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000628:therapy; D007850:Lauric Acids; D008297:Male; D009218:Myosins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D054460:rho-Associated Kinases / Q000378:metabolism*
D007850:Lauric Acids; D047428:Protein Kinase Inhibitors; C431085:hydroxyfasudil; C030358:lauric acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D009218:Myosins; C049347:fasudil; D000983:Antipyrine; C008135:iodoantipyrine