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 language | English |
|---|---|
| Pages (from-to) | 2028-2040 |
| Number of pages | 13 |
| Journal | Journal of Neuroscience Research |
| Volume | 89 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2011 |
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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 journal › Article
}
TY - JOUR
T1 - Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes
AU - Alvarez, Veronica M.
AU - Rama Rao, Kakulavarapu V.
AU - Brahmbhatt, Monica
AU - Norenberg, Michael D
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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.
AB - 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.
KW - Ammonia
KW - Astrocyte swelling
KW - Brain edema
KW - Cytokines
KW - Hemeoxygenase-1
KW - Hepatic encephalopathy
KW - Inflammation
KW - Mitochondrial permeability transition
KW - Oxidative/nitrosative stress
UR - http://www.scopus.com/inward/record.url?scp=80053647234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053647234&partnerID=8YFLogxK
U2 - 10.1002/jnr.22708
DO - 10.1002/jnr.22708
M3 - Article
C2 - 21748779
AN - SCOPUS:80053647234
VL - 89
SP - 2028
EP - 2040
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 12
ER -