Abstract
Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver disease. While the pathogenesis of HE is unclear, elevated blood and brain ammonia levels are believed to be major etiological factors, and astrocytes appear to be the primary target of its toxicity. A notable feature of ammonia neurotoxicity is an upregulation of the 18-kDa translocator protein (TSPO) (formerly referred to as the peripheral benzodiazepine receptor or PBR), which is found on the outer mitochondrial membrane. However, the precise significance of this upregulation is unclear. To examine its potential role in ammonia-induced astrocyte dysfunction, we downregulated the TSPO using antisense oligonucleotides, and examined whether such downregulation could alter two prominent features of ammonia gliotoxicity, namely, the mitochondrial permeability transition (MPT) and astrocyte swelling. Nontransfected cultures treated with NH4Cl (5 mM; 48 h) showed a significant increase in astrocyte cell volume (37.5%). In cultured astrocytes transfected with TSPO antisense oligonucleotides, such cell swelling was reduced to 17%, but this change was not significantly different from control cell volume. Similarly, nontransfected cultures treated with NH4Cl (5 mM; 24 h) exhibited a 40% decline in the cyclosporin A-sensitive mitochondrial inner membrane potential (ΔΨm) (P < 0.01) (a measure of the MPT). By contrast, cells transfected with TSPO antisense oligonucleotides did not display a significant loss of the ΔΨm following ammonia exposure. Our findings highlight the important role of the TSPO in the mechanism of ammonia neurotoxicity.
| Original language | English |
|---|---|
| Pages (from-to) | 1720-1727 |
| Number of pages | 8 |
| Journal | GLIA |
| Volume | 55 |
| Issue number | 16 |
| DOIs | |
| State | Published - Dec 1 2007 |
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Keywords
- 18-kDa translocator protein
- Ammonia toxicity
- Astrocytes
- Cell swelling
- Hepatic encephalopathy
- Mitochondrial permeability transition
- Peripheral benzodiazepine receptor
ASJC Scopus subject areas
- Immunology
Cite this
Downregulation of the 18-kDa translocator protein : Effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. / Panickar, K. S.; Jayakumar, A. R.; Rama Rao, K. V.; Norenberg, Michael D.
In: GLIA, Vol. 55, No. 16, 01.12.2007, p. 1720-1727.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Downregulation of the 18-kDa translocator protein
T2 - Effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes
AU - Panickar, K. S.
AU - Jayakumar, A. R.
AU - Rama Rao, K. V.
AU - Norenberg, Michael D
PY - 2007/12/1
Y1 - 2007/12/1
N2 - Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver disease. While the pathogenesis of HE is unclear, elevated blood and brain ammonia levels are believed to be major etiological factors, and astrocytes appear to be the primary target of its toxicity. A notable feature of ammonia neurotoxicity is an upregulation of the 18-kDa translocator protein (TSPO) (formerly referred to as the peripheral benzodiazepine receptor or PBR), which is found on the outer mitochondrial membrane. However, the precise significance of this upregulation is unclear. To examine its potential role in ammonia-induced astrocyte dysfunction, we downregulated the TSPO using antisense oligonucleotides, and examined whether such downregulation could alter two prominent features of ammonia gliotoxicity, namely, the mitochondrial permeability transition (MPT) and astrocyte swelling. Nontransfected cultures treated with NH4Cl (5 mM; 48 h) showed a significant increase in astrocyte cell volume (37.5%). In cultured astrocytes transfected with TSPO antisense oligonucleotides, such cell swelling was reduced to 17%, but this change was not significantly different from control cell volume. Similarly, nontransfected cultures treated with NH4Cl (5 mM; 24 h) exhibited a 40% decline in the cyclosporin A-sensitive mitochondrial inner membrane potential (ΔΨm) (P < 0.01) (a measure of the MPT). By contrast, cells transfected with TSPO antisense oligonucleotides did not display a significant loss of the ΔΨm following ammonia exposure. Our findings highlight the important role of the TSPO in the mechanism of ammonia neurotoxicity.
AB - Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver disease. While the pathogenesis of HE is unclear, elevated blood and brain ammonia levels are believed to be major etiological factors, and astrocytes appear to be the primary target of its toxicity. A notable feature of ammonia neurotoxicity is an upregulation of the 18-kDa translocator protein (TSPO) (formerly referred to as the peripheral benzodiazepine receptor or PBR), which is found on the outer mitochondrial membrane. However, the precise significance of this upregulation is unclear. To examine its potential role in ammonia-induced astrocyte dysfunction, we downregulated the TSPO using antisense oligonucleotides, and examined whether such downregulation could alter two prominent features of ammonia gliotoxicity, namely, the mitochondrial permeability transition (MPT) and astrocyte swelling. Nontransfected cultures treated with NH4Cl (5 mM; 48 h) showed a significant increase in astrocyte cell volume (37.5%). In cultured astrocytes transfected with TSPO antisense oligonucleotides, such cell swelling was reduced to 17%, but this change was not significantly different from control cell volume. Similarly, nontransfected cultures treated with NH4Cl (5 mM; 24 h) exhibited a 40% decline in the cyclosporin A-sensitive mitochondrial inner membrane potential (ΔΨm) (P < 0.01) (a measure of the MPT). By contrast, cells transfected with TSPO antisense oligonucleotides did not display a significant loss of the ΔΨm following ammonia exposure. Our findings highlight the important role of the TSPO in the mechanism of ammonia neurotoxicity.
KW - 18-kDa translocator protein
KW - Ammonia toxicity
KW - Astrocytes
KW - Cell swelling
KW - Hepatic encephalopathy
KW - Mitochondrial permeability transition
KW - Peripheral benzodiazepine receptor
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UR - http://www.scopus.com/inward/citedby.url?scp=35348973583&partnerID=8YFLogxK
U2 - 10.1002/glia.20584
DO - 10.1002/glia.20584
M3 - Article
VL - 55
SP - 1720
EP - 1727
JO - GLIA
JF - GLIA
SN - 0894-1491
IS - 16
ER -