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 language | English |
|---|---|
| Pages (from-to) | 2677-2685 |
| Number of pages | 9 |
| Journal | Journal of Neuroscience Research |
| Volume | 87 |
| Issue number | 12 |
| DOIs | |
| State | Published - Sep 1 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes
AU - Reddy, Pichili V B
AU - Rama Rao, Kakulavarapu V.
AU - Norenberg, Michael D
PY - 2009/9/1
Y1 - 2009/9/1
N2 - 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.
AB - 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.
KW - Ammonia
KW - Astrocyte swelling
KW - Brain edema
KW - Mitochondrial permeability transition
UR - http://www.scopus.com/inward/record.url?scp=70449497896&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70449497896&partnerID=8YFLogxK
U2 - 10.1002/jnr.22097
DO - 10.1002/jnr.22097
M3 - Article
VL - 87
SP - 2677
EP - 2685
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 12
ER -