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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
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 304:1042-1047
- Publication Year :
- 2002
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2002.
-
Abstract
- 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.
- Subjects :
- Male
Cell Membrane Permeability
Indazoles
Calmodulin
Brain Edema
Trifluoperazine
Pharmacology
chemistry.chemical_compound
Animals
Medicine
Rats, Wistar
Stroke
Barrier function
Evans Blue
biology
business.industry
Antagonist
Water
medicine.disease
Extravasation
Rats
Endothelial stem cell
Disease Models, Animal
chemistry
Blood-Brain Barrier
Ischemic Attack, Transient
Anesthesia
biology.protein
Molecular Medicine
Endothelium, Vascular
business
medicine.drug
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 304
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....22d96e958d1c54cc6249ff4b93611526