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Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes
Author(s) -
Alvarez Veronica M.,
Rama Rao Kakulavarapu V.,
Brahmbhatt Monica,
Norenberg Michael D.
Publication year - 2011
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22708
Subject(s) - mitochondrial permeability transition pore , oxidative stress , downregulation and upregulation , tumor necrosis factor alpha , chemistry , cytokine , pharmacology , ammonia , mitochondrion , inflammation , biology , apoptosis , biochemistry , immunology , programmed cell death , gene
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. © 2011 Wiley‐Liss, Inc.