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

Research output: Contribution to journalArticle

23 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)28-37
Number of pages10
JournalTranslational stroke research
Volume5
Issue number1
DOIs
StatePublished - Feb 2014

Keywords

  • Acute liver failure
  • Ammonia
  • Astrocyte swelling
  • Brain edema
  • Glibenclamide
  • NCCa-ATP channel
  • Sulfonylurea receptor type 1 protein

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Cardiology and Cardiovascular Medicine

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