Positive feedback role of TRPC3 in TNF-α-mediated vasogenic edema formation induced by status epilepticus independent of ETBreceptor activation.
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-α inhibitor), SN50 (a nuclear factor-κB (NFκB) 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 NFκB p65-Thr435 phosphorylation and ETBreceptor expression. In addition, Pyr-3 mitigated NFκB p65-Thr435 phosphorylation induced by recombinant TNF-α. These findings indicate that TNF-α-mediated NFκB 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 ETBreceptor activation. Therefore, we suggest that TRPC3 may be involved in a positive feedback loop of NFκB/ETBreceptor signaling pathway.
Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, South Korea.
Su-Ji
SJ
Min
Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, South Korea. Electronic address: tckang@hallym.ac.kr.
Tae-Cheon
TC
Kang
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D014409:Tumor Necrosis Factor-alpha; C086539:BQ 788; D052250:Nitric Oxide Synthase Type III
ET-1; NFκB; Pyr-3; TNF-α; TRPC3; status epilepticus