POSITIVE FEEDBACK ROLE OF TRPC3 IN TNF-alpha-MEDIATED VASOGENIC EDEMA FORMATION INDUCED BY STATUS EPILEPTICUS INDEPENDENT OF ETB RECEPTOR ACTIVATION

摘要

Brain-blood barrier (BBB) disruption results in vasogenic edema, which is involved in the pathogenesis of epilepsy. Following status epilepticus (SE), up-regulated transient receptor potential canonical channel-3 (TRPC3), a Ca2+ -permeable cation channels in endothelial cells, is relevant to vasogenic edema formation in the rat piriform cortex. In addition, pyrazole-3 (Pyr-3, a TRPC3 inhibitor) attenuated SE-induced vasogenic edema. However, the upstream regulators of TRPC3 expression in vasogenic edema formation have been unclear. In the present study, soluble tumor necrosis factor p55 receptor (sTNFp55R, a TNF-alpha inhibitor), SN50 (a nuclear factor-kappa B (NF kappa B) inhibitor), BQ-788 (an endothelin B (ETB) receptor inhibitor) and Pyr-3 effectively prevented vasogenic edema following SE. sTNFp55R and SN50 (but not BQ-788) attenuated SE-induced up-regulation of endothelial TRPC3 expression. Pyr-3 ameliorated SE-induced NF kappa B p65-Thr435 phosphorylation and ETB receptor expression. In addition, Pyr-3 mitigated NF kappa B p65-Thr435 phosphorylation induced by recombinant TNF-alpha. These findings indicate that TNF-alpha-mediated NF kappa B p65-Thr435 phosphorylation may up-regulate TRPC3 expression, which participates in vasogenic edema formation via increasing endothelial nitric oxide synthase expression following SE, independent of ETB receptor activation. Therefore, we suggest that TRPC3 may be involved in a positive feedback loop of NF kappa B/ETB receptor signaling pathway. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.