DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra.
Abstract
Previous studies have indicated that volume regulated anion channels (VRACs) may be involved in the pathology of the ischemic brain cortical penumbra due to activation of VRAC-mediated excitatory amino-acid (EAA) release. To assess this we had studied neuroprotection and EAA release inhibition by a potent VRAC inhibitor, tamoxifen. However, tamoxifen inhibits several other neurodamaging processes. In the present study we use an ethacrynic acid derivative, 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), that has recently been shown to be a specific antagonist of volume regulated anion channels (VRAC), to measure the extent of neuroprotection provided and thus to better assess the role of VRAC-mediated release of excitatory amino acids in an intraluminal suture, reversible middle cerebral artery occlusion (rMCAO) model in adult rats. Rats given DCPIB intracisternally had significantly better neurobehavioral scores after 24 h and showed significantly reduced infarct volumes. Mean infarct volumes were 208.0 (SD=38.3) mm3 for the vehicle groups, compared with 68.5 (SD=22.7) mm3 for intracisternally DCPIB-treated groups (p=0.02, Mann-Whitney test), a reduction of around 75%. However, a 500-fold higher ...Continue Reading
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