Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes

Pichili V B Reddy, Kakulavarapu V. Rama Rao, Michael D Norenberg

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Ammonia is the principal neurotoxin implicated in the pathogenesis of hepatic encephalopathy, and astrocytes are the neural cells predominantly affected in this condition. Astrocyte swelling (cytotoxic edema) represents a critical component of the brain edema in acute form of hepatic encephalopathy (acute liver failure, ALF). Although mechanisms of astrocyte swelling by ammonia are not completely understood, cultured astrocytes exposed to pathophysiological levels of ammonia develop the mitochondrial permeability transition (mPT), a process that was shown to result in astrocyte swelling. Cyclosporin A (CsA), a traditional inhibitor of the mPT, was previously shown to completely block ammonia-induced astrocyte swelling in culture. However, the efficacy of CsA to protect cytotoxic brain edema in ALF is problematic because it poorly crosses the blood-brain barrier, which is relatively intact in ALF. We therefore examined the effect of agents that block the mPT but are also known to cross the blood-brain barrier, including pyruvate, magnesium, minocycline, and trifluoperazine on the ammonia-induced mPT, as well as cell swelling. Cultured astrocytes exposed to ammonia for 24 hr displayed the mPT as demonstrated by a CsAsensitive dissipation of the mitochondrial inner membrane potential. Pyruvate, minocycline, magnesium, and trifluoperazine significantly blocked the ammoniainduced mPT. Ammonia resulted in a significant increase in cell volume, which was blocked by the above-mentioned agents to a variable degree. A regression analysis indicated a high correlation between the effectiveness of reducing the mPT and cell swelling. Our data suggest that all these agents have therapeutic potential in mitigating brain edema in ALF.

Original languageEnglish
Pages (from-to)2677-2685
Number of pages9
JournalJournal of Neuroscience Research
Volume87
Issue number12
DOIs
StatePublished - Sep 1 2009

Fingerprint

Ammonia
Astrocytes
Permeability
Acute Liver Failure
Brain Edema
Trifluoperazine
Minocycline
Hepatic Encephalopathy
Blood-Brain Barrier
Pyruvic Acid
Magnesium
Cyclosporine
Mitochondrial Membrane Potential
Neurotoxins
Cell Size
Edema
Regression Analysis

Keywords

  • Ammonia
  • Astrocyte swelling
  • Brain edema
  • Mitochondrial permeability transition

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes. / Reddy, Pichili V B; Rama Rao, Kakulavarapu V.; Norenberg, Michael D.

In: Journal of Neuroscience Research, Vol. 87, No. 12, 01.09.2009, p. 2677-2685.

Research output: Contribution to journalArticle

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