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-α-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.
Footnotes
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DOI: 10.1124/jpet.102.045039
- Abbreviations:
- BBB
- blood-brain barrier
- TNFα
- tumor necrosis factor-α
- MCA
- middle cerebral artery
- MRI
- magnetic resonance imaging
- HBMEC
- human brain microvascular endothelial cell
- ANOVA
- analysis of variance
- PLSD
- protected least significant difference
- NOS
- nitric-oxide synthase
- A23187
- 5-(methylamino)-2-[(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H)-pyrrol-2-yl)-ethyl]-1,7-dioxaspiro[5,5] undec-2-yl]methyl]-4-benzoxazolecarboxylic acid
- Received October 2, 2002.
- Accepted November 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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