3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e),a novel calmodulin antagonist,reduces brain edema through the inhibition of enhanced blood-brain barrier pe

摘要

An alteraction of the blood-brain barrier(BBB) permeability contributes to the development of brain edema after stoke.In this study,we evaluated the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate 9DY-9760e),a novel calmodulin antagonsit,on brain edema formation and BBB integrity in rats subjected to transient focal ischemia.DY-9760e (1 mg/kg/h) was intravenously infused for 6 h,starting immediately after reperfusion of a 1-h middle cerebral artery occlusion.Treatment with DY-9760e significantly suppressed the increase in water content and the extravasation of Evans blue dye after tansient focalischemia.Analysis of a magnetic resonance imaging method revealed that DY-9760e significantly prevented the development of brain edema in the cortical region of the ipsilateral hemisphere.Trifluoperazine,a calmodulin antagonsit that is structurally different from DY-9760e,also attenuated brain edema elicited by transient focalischemia.Furthermore,DY-9760e and trifluoperazine reduced tumor necrosis facgor-alpha-induced hyperpermeability of inulin through a cultured brain microvascular endothelial cell monolayer,suggesting an involvementof calmodulin in the regulation of brain microvascular barrier function. The present results demonstrate that DY-9760e ameliorates brain edema formation and suggest that this effect may be mediated inpart by the inhibition of enhanced BBB permeability after ischemic insults.Thus,DY-9760e is expected to be a therapeutic drug for treatment of acute stroke patients.