Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure

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 syst...

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Bibliographic Details
Published in:Translational stroke research 2014-02, Vol.5 (1), p.28-37
Main Authors: Jayakumar, A. R., Valdes, V., Tong, X. Y., Shamaladevi, N., Gonzalez, W., Norenberg, M. D.
Format: Article
Language:English
Subjects:
Ammonia
Ammonia - pharmacology
Animals
Astrocytes - cytology
Astrocytes - drug effects
Astrocytes - metabolism
Biomedical and Life Sciences
Biomedicine
Brain
Brain Edema - metabolism
Cardiology
Cell Size - drug effects
Cells, Cultured
Coma
Edema
Glyburide - pharmacology
Hypoglycemic Agents - pharmacology
Ion Channels - metabolism
Liver
Liver Failure, Acute - metabolism
Neurology
Neurosciences
Neurosurgery
Original Article
Pathogenesis
Proteins
Rats
Sulfonylurea Receptors - metabolism
Vascular Surgery
Water measurement
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Summary: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 ammonia-treated 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. 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.
ISSN:1868-4483
1868-601X
DOI:10.1007/s12975-014-0328-z