Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure
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ORIGINAL ARTICLE
Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure A. R. Jayakumar & V. Valdes & X. Y. Tong & N. Shamaladevi & W. Gonzalez & M. D. Norenberg
Received: 19 August 2013 / Revised: 3 January 2014 / Accepted: 5 January 2014 / Published online: 18 January 2014 # Springer Science+Business Media New York 2014
Abstract Astrocyte swelling (cytotoxic brain edema) is the major neurological complication of acute liver failure (ALF), a condition in which ammonia has been strongly implicated in its etiology. Ion channels and transporters are known to be involved in cell volume regulation, and a disturbance in these systems may result in cell swelling. One ion channel known to contribute to astrocyte swelling/brain edema in other neurological disorders is the ATP-dependent, nonselective cation (NCCa-ATP) channel. We therefore examined its potential role in the astrocyte swelling/brain edema associated with ALF. Cultured astrocytes treated with 5 mM ammonia showed a threefold increase in the sulfonylurea receptor type 1 (SUR1) protein expression, a marker of NCCa-ATP channel activity. Blocking SUR1 with glibenclamide significantly reduced the ammonia-induced cell swelling in cultured astrocytes. Additionally, overexpression of SUR1 in ammoniatreated cultured astrocytes was significantly reduced by cotreatment of cells with BAY 11–7082, an inhibitor of NF-κB, indicating the involvement of an NF-κB-mediated SUR1 upregulation in the mechanism of ammonia-induced astrocyte swelling. Brain SUR1 mRNA level was also found to be increased in the thioacetamide (TAA) rat model of ALF. A. R. Jayakumar : V. Valdes : W. Gonzalez : M. D. Norenberg (*) Department of Pathology, University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101, USA e-mail: [email protected] A. R. Jayakumar : X. Y. Tong : M. D. Norenberg Veterans Affairs Medical Center, Miami, FL, USA N. Shamaladevi Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA M. D. Norenberg Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Additionally, we found a significant increase in SUR1 protein expression in rat brain cortical astrocytes in TAA-treated rats. Treatment with glibenclamide significantly reduced the brain edema in this model of ALF. These findings strongly suggest the involvement of NCCa-ATP channel in the astrocyte swelling/brain edema in ALF and that targeting this channel may represent a useful approach for the treatment of the brain edema associated with ALF. Keywords Ammonia . Acute liver failure . Astrocyte swelling . Brain edema . Glibenclamide . NCCa-ATP channel . Sulfonylurea receptor type 1 protein
Introduction Hepatic encephalopathy (HE) is a clinical condition that occurs in patients with severe liver disease. Acute HE (acute liver failure, ALF) is a life-threatening condition associated with the sudden onset of seizures, delirium, and coma, generally occurring after viral hepatit
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