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 permeability after transient focal ischemia.
An alteration of the blood-brain barrier (BBB) permeability contributes to the development of brain edema after stroke. 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 (DY-9760e), a novel calmodulin antagonist, 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 transient focal ischemia. 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 antagonist that is structurally different from DY-9760e, also attenuated brain edema elicited by transient focal ischemia. Furthermore, DY-9760e and trifluoperazine reduced tumor necrosis factor-alpha-induced hyperpermeability of inulin through a cultured brain microvascular endothelial cell monolayer, suggesting an involvement of 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 in part 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.
Sato
Toshiyuki
T
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Morishima
Yoshiyuki
Y
Shirasaki
Yasufumi
Y
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D007191:Indazoles / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000150:complications*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014268:Trifluoperazine / Q000494:pharmacology; D014867:Water / Q000378:metabolism
C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D002147:Calmodulin; D007191:Indazoles; D014867:Water; D014268:Trifluoperazine