Effects of ammonia onl-glutamate uptake in cultured astrocytes

Bender, Alex S.; Norenberg, Michael D.

doi:10.1007/bf02527755

Cited by 81 publications

(60 citation statements)

References 40 publications

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“…This is accomplished in the astrocyte via glutamine synthetase (GS). Glutamine is osmotically active and can cause astrocytic swelling leading to cytotoxic oedema (Batshaw et al 1986;Bender and Norenberg 1996;Norenberg 1996;Norenberg et al 2005). Studies in which the GS inhibitor methionine sulfoximine is administered demonstrate reduced ammonia-induced brain oedema in both in vivo (Takahashi et al 1991) and in vitro models (Blei et al 1994;Norenberg and Bender 1994;Takahashi et al 1991).…”

Section: Pathogenic Mechanisms Of Acute Hyperammonaemiamentioning

confidence: 99%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

191

152

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SummaryThe urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1 H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

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Section: Pathogenic Mechanisms Of Acute Hyperammonaemiamentioning

confidence: 99%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

191

152

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“…Thus, whereas total brain glutamate levels are decreased in various models of HE (Hindfelt et al, 1977;Bosman et al, 1990;Dejong et al, 1992), extracellular glutamate levels are consistently increased in rat models of acute liver failure (Moroni et al, 1983;Tossman et al, 1987;de Knegt et al, 1994). Ammonia has been shown to suppress high affinity glutamate uptake (Bender and Norenberg, 1996). Likewise, downregulation of the glutamate transporter GLT-1 [excitatory amino acid transporter 2 (EAAT-2)] has been shown in hyperammonemic rats, in rats with portacaval anastomosis (model of chronic HE), as well as in thioacetamide-induced acute liver failure (Knecht et al, 1997;Norenberg et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Jayakumar¹,

Panickar

Murthy³

et al. 2006

J. Neurosci.

192

158

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Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver failure. Elevated levels of ammonia have been strongly implicated as a factor in HE, and astrocytes appear to be the primary target of its neurotoxicity. Mechanisms mediating key aspects of ammonia-induced astrocyte dysfunction such as cell swelling and inhibition of glutamate uptake are not clear. We demonstrated previously that cultured astrocytes exposed to ammonia increase free radical production. We now show that treatment with antioxidants significantly prevents ammonia-induced astrocyte swelling as well as glutamate uptake inhibition. Because one consequence of oxidative stress is the phosphorylation of mitogen-activated protein kinases (MAPKs), we investigated whether phosphorylation of MAPKs may mediate astrocyte dysfunction. Primary cultured astrocytes exposed to 5 mM NH 4 Cl for different time periods (1-72 h) significantly increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK , and c-Jun N-terminal kinase (JNK) 1/2/3, which was inhibited by appropriate MAPK inhibitors 1, 4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (UO126; for ERK1/2), trans-1-(4-hydroxyclyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole (SB 239063; for p38MAPK ), and anthra[1,9-cd]pyrazol-6(2H)-one (SP600125; for JNK1/2/3), as well as by antioxidants. Kinase inhibitors partially or completely prevented astrocyte swelling. Although SB239063 and SP600125 significantly reversed glutamate uptake inhibition and ammonia-induced decline in glutamate-aspartate transporter protein levels, UO126 did not, indicating a differential effect of these kinases in ammonia-induced astrocyte swelling and glutamate transport impairment. These studies strongly suggest the involvement of oxidative stress and phosphorylation of MAPKs in the mechanism of ammonia-induced astrocyte dysfunction associated with ammonia neurotoxicity.

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“…Decreased glutamate uptake was described in synaptosomal preparations from rats with experimental ALF (Oppong et al, 1995). Furthermore, exposure of primary cultured astrocytes to millimolar concentrations of ammonia also resulted in a significant reduction in uptake of [ 3 H]-D-aspartate (Bender and Norenberg, 1996). In extracts from cerebral cortex of rats in coma stages of encephalopa-thy following hepatic devascularization, a significant loss of GLT-1 (EAAT-2) protein and gene expression was observed (Knecht et al, 1997).…”

Section: Inhibition Of Glutamate Uptakementioning

confidence: 99%

Untitled

Rose

2002

Metabolic Brain Disease

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Glutamatergic dysfunction has been suggested to play an important role in the pathogenesis of hepatic encephalopathy (HE) in acute liver failure (ALF). Increased extracellular brain glutamate concentrations have consistently been described in different experimental animal models of ALF and in patients with increased intracranial pressure due to ALF. High brain ammonia levels remain the leading candidate in the pathogenesis of HE in ALF and studies have demonstrated a correlation between ammonia and increased concentrations of extracellular brain glutamate both clinically and in experimental animal models of ALF. Inhibition of glutamate uptake or increased glutamate release from neurons and/or astrocytes could cause an increase in extracellular glutamate. This review analyses the effect of ammonia on glutamate release from (and uptake into) both neurons and astrocytes and how these pathophysiological mechanisms may be involved in the pathogenesis of HE in ALF.

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Effects of ammonia onl-glutamate uptake in cultured astrocytes

Cited by 81 publications

References 40 publications

Neurological implications of urea cycle disorders

Neurological implications of urea cycle disorders

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

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