Rho kinase (ROCK), one of the
serine/threonine kinases, is involved in pathologic conditions, and its activation causes neuronal cell death.
Fasudil, a selective ROCK inhibitor, has been reported to cause increased cerebral blood flow (CBF) in the ischemic brain and protect against neuronal cell death by inhibiting ROCK.
Ozagrel, a
thromboxane A(2) synthase inhibitor, inhibits platelet aggregation and causes vasodilatation, thereby increasing CBF in
cerebral thrombosis. The present study evaluates the combination
therapy of
fasudil and
ozagrel on focal
brain ischemia induced by
middle cerebral artery occlusion (MCAO) in mice. Each monotherapy of
fasudil at 10 mg/kg i.p. and
ozagrel at 30 mg/kg i.p. significantly reduced
cerebral infarction. The combination
therapy of
fasudil (3 mg/kg i.p.) and
ozagrel (10 mg/kg i.p.), which are noneffective doses, resulted in reduction of
cerebral infarction, and the protective effect was observed up to 5 min, but not 3 h, after reperfusion. Regional CBF after MCAO and phosphorylation of
endothelial nitric-oxide synthase (NOS) significantly increased in response to the combination
therapy, whereas these effects were not observed with monotherapy of either
drug. The protective effect of combination treatment was antagonized by the treatment of a NOS inhibitor, nitro-
l-arginine methyl ester hydrochloride. These findings indicate that the combination treatment of
fasudil and
ozagrel exhibits additive effects for neuroprotection after MCAO. These findings indicate that the combination treatment of
fasudil and
ozagrel may be useful as a potential therapeutic strategy for the treatment of
stroke.