Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes

Veronica M. Alvarez, Kakulavarapu V. Rama Rao, Monica Brahmbhatt, Michael D Norenberg

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Hepatic encephalopathy (HE) is the major neurological complication occurring in patients with acute and chronic liver failure. Elevated levels of blood and brain ammonia are characteristic of HE, and astrocytes are the primary target of ammonia toxicity. In addition to ammonia, recent studies suggest that inflammation and associated cytokines (CKs) also contribute to the pathogenesis of HE. It was previously established that ammonia induces the mitochondrial permeability transition (mPT) in cultured astrocytes. As CKs have been shown to cause mitochondrial dysfunction in other conditions, we examined whether CKs induce the mPT in cultured astrocytes. Cultures treated with tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ, individually or in a mixture, resulted in the induction of the mPT in a time-dependent manner. Simultaneous treatment of cultures with a mixture of CKs and ammonia showed a marked additive effect on the mPT. As oxidative stress (OS) is known to induce the mPT, so we examined the effect of CKs and ammonia on hemeoxygenase-1 (HO-1) protein expression, a marker of OS. Such treatment displayed a synergistic effect in the upregulation of HO-1. Antioxidants significantly blocked the additive effects on the mPT by CKs and ammonia, suggesting that OS represents a major mechanism in the induction of the mPT. Treatment of cultures with minocycline, an antiinflammatory agent, which is known to inhibit OS, also diminished the additive effects on the mPT caused by CKs and ammonia. Induction of the mPT in astrocytes appears to represent a major pathogenetic factor in HE, in which CKs and ammonia are critically involved.

Original languageEnglish
Pages (from-to)2028-2040
Number of pages13
JournalJournal of Neuroscience Research
Volume89
Issue number12
DOIs
StatePublished - Dec 1 2011

Fingerprint

Ammonia
Astrocytes
Permeability
Cytokines
Hepatic Encephalopathy
Oxidative Stress
Heme Oxygenase-1
Minocycline
End Stage Liver Disease
Acute Liver Failure
Interleukin-1
Interferons
Interleukin-6
Anti-Inflammatory Agents
Up-Regulation
Therapeutics
Tumor Necrosis Factor-alpha
Antioxidants
Inflammation
Brain

Keywords

  • Ammonia
  • Astrocyte swelling
  • Brain edema
  • Cytokines
  • Hemeoxygenase-1
  • Hepatic encephalopathy
  • Inflammation
  • Mitochondrial permeability transition
  • Oxidative/nitrosative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. / Alvarez, Veronica M.; Rama Rao, Kakulavarapu V.; Brahmbhatt, Monica; Norenberg, Michael D.

In: Journal of Neuroscience Research, Vol. 89, No. 12, 01.12.2011, p. 2028-2040.

Research output: Contribution to journalArticle

Alvarez, Veronica M. ; Rama Rao, Kakulavarapu V. ; Brahmbhatt, Monica ; Norenberg, Michael D. / Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. In: Journal of Neuroscience Research. 2011 ; Vol. 89, No. 12. pp. 2028-2040.
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