Abstract
Status epilepticus (SE) induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB). However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB) receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-α (TNF-α) stimulated endothelin-1 (ET-1) release and expression in neurons and endothelial cells. In addition, TNF-α-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS) activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-α-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / metabolism
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Astrocytes / pathology
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Blood-Brain Barrier / metabolism*
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Blood-Brain Barrier / pathology
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Brain Edema / etiology
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Brain Edema / genetics
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Brain Edema / metabolism*
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Brain Edema / pathology
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology
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Disease Models, Animal
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Endothelin-1 / genetics
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Endothelin-1 / metabolism*
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Gene Expression Regulation
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Male
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Microdialysis
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Neurons / metabolism
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Neurons / pathology
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Receptor, Endothelin A / genetics
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Receptor, Endothelin A / metabolism*
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Signal Transduction
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Status Epilepticus / complications
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Status Epilepticus / genetics
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Status Epilepticus / metabolism*
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Status Epilepticus / pathology
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Stereotaxic Techniques
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Endothelin-1
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Reactive Oxygen Species
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Receptor, Endothelin A
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Tumor Necrosis Factor-alpha
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Nitric Oxide Synthase Type III
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Nos3 protein, rat
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NADPH Oxidases
Grants and funding
This study was supported by grants from the Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs (Grant number A111313) and the National Research Foundation of Korea (MEST No. 2012R1A2A1A01001775), funded by the Korean government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.