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.