Portal-Systemic Encephalopathy: A Disorder of Neuron-Astrocytic Metabolic Trafficking

Butterworth, Roger F.

doi:10.1159/000111350

Cited by 57 publications

(31 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

Section: Western Blottingsupporting

confidence: 55%

“…Reduced expression of GLT-1 and the consequently increased extracellular brain glutamate concentrations also offers a possible explanation for the observed decrease in densities (down regulation) of AMPA/kainate binding sites also described in this model of acute liver failure [10]. Diminished uptake of neuronally released glutamate by the astrocyte as a consequence of decreased expression of GLT-1 would therefore constitute further evidence of impaired neuron-astrocytic trafficking of glutamate, a phenomenon which has previously been proposed to contribute to the pathogenesis of hepatic encephalopathy based on neurochemical studies [4]and by 13C-NMR spectroscopy [16]in portacaval-shunted rats.Impaired removal of glutamate from brain extracellular space due to decreased GLT-1 expression could also be implicated in the pathogenesis of cytotoxic brain edema, a major complication of acute liver failure in both humans and in the experimental animal model used in the present study [17]. Exposure of cultured astrocytes to glutamate leads to significant cell swelling [15].…”

supporting

confidence: 55%

See 1 more Smart Citation

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure

Knecht

Michalak

Rose

et al. 1997

Neuroscience Letters

169

View full text Add to dashboard Cite

Knecht, K. et al., 1997. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neuroscience Letters, 229(3), The final publication is available at http://dx.doi.org/10.1016/S0304-3940 (97) ABSTRACTIt has been suggested that reduced astrocytic uptake of neuronally released glutamate contributes to the pathogenesis of hepatic encephalopathy in acute liver failure. In order to further address this issue, the recently cloned and sequenced astrocytic glutamate transporter GLT-1 was studied in brain preparations from rats with ischemic liver failure induced by portacaval anastomosis followed 24 h later by hepatic artery ligation and from appropriate sham-operated controls. GLT-1 expression was studied using reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of GLT-1 transcript was significantly decreased in frontal cortex at coma stages of acute liver failure. Western blotting using a polyclonal antibody to GLT-1 revealed a concomitant decrease in expression of transporter protein in the brains of rats with acute liver failure. Reduced capacity of astrocytes to reuptake neuronally released glutamate, resulting from a GLT-1 transporter deficit and the consequently compromised neuron-astrocytic trafficking of glutamate could contribute to the pathogenesis of hepatic encephalopathy and brain edema, two major complications of acute liver failure.Keywords GLT-1; hepatic encephalopathy; Astrocytes; Neuron-astrocyte trafficking; Gene expression; RT-PCR; Western blottingAcute liver failure resulting from viral infections or ingestion of toxic substances results in severe neurological impairment progressing through stupor and coma within hours or days. The pathophysiologic mechanisms responsible for hepatic encephalopathy (HE) in acute liver failure are unknown but deficits of neurotransmission rather than primary cerebral energy failure are currently considered to be implicated [1 and 3]. In this regard, there is increasing evidence to suggest that abnormalities of the glutamate neurotransmitter system are involved in the pathogenesis of HE in acute liver failure. Brain concentrations of glutamate are reduced in both human [13]and experimental [7 and 17] acute liver failure and recent studies using in vivo cerebral microdialysis in both rats 2 and 9and rabbits [5]with acute (ischemic) liver failure have consistently revealed increased extracellular brain concentrations of glutamate. It was suggested that the increased extracellular concentrations of glutamate in the brain of these animals was the consequence of decreased astrocytic uptake [9]. The major high affinity astrocytic transporter for glutamate, GLT-1, has recently been cloned and sequenced 12 and 14. In order to directly assess glutamate uptake capacity in the brain in acute liver failure, GLT-1 gene and protein expression were measured in frontal cortex of rats with acute (ischemic) liver failure.Male, Sprague-Dawley rats (175-200 g) were anesthetized with halothane and an end-to-side portacaval ...

show abstract

Section: Western Blottingsupporting

confidence: 55%

supporting

confidence: 55%

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure

Knecht

Michalak

Rose

et al. 1997

Neuroscience Letters

169

View full text Add to dashboard Cite

show abstract

“…The absence of an NH 4 Cl effect on mature axons could be attributable to fully differentiated astrocytes, which have a higher capacity for ammonium detoxification (Butterworth, 1993). Alternatively, protective factors released by target postsynaptic neurons to their presynaptic counterparts could be involved (Keith and Wilson, 2001).…”

Section: Nh 4 CL Exposure Does Not Alter Axonal Morphology In Mature mentioning

confidence: 99%

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Braissant¹,

Henry²,

Villard³

et al. 2002

J. Neurosci.

100

137

View full text Add to dashboard Cite

Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH 4 Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.

show abstract

“…The glutamine-glutamate-cycle [22] is completed when glutamate, which is released from synaptic vesicles, is taken up by astrocytes again and converted to glutamine. Astrocytes are therefore involved in replenishing neurotransmitter pools [23], and a rise in glutamine synthesis may affect the normal metabolic balance between astrocytes and neurons [24,25]. Accumulation of glutamine, which causes brain edema [26,27], or long exposure of astrocytes to NH + 4 , is accompanied by a decrease in myo-inositol [12,14,[28][29][30], an important organic osmolyte [31], which is highly concentrated in glial cells [32].…”

Section: Introductionmentioning

confidence: 99%

Multinuclear NMR Spectroscopy Studies on NH<sub>4</sub>Cl-Induced Metabolic Alterations and Detoxification Processes in Primary Astrocytes and Glioma Cells

et al. 1998

View full text Add to dashboard Cite

Glutamine synthesis, the major pathway of ammonia detoxification, and the intracellular concentration of organic osmolytes in primary astrocytes and F98 glioma cells were investigated with multinuclear magnetic resonance spectroscopy. Acute exposure to ammonia (3 h incubation with NH₄Cl) raised the concentration of glutamine and other amino acids, such as glutamate and aspartate, and decreased myo-inositol, hypotaurine, and taurine concentrations. The loss of these osmolytes was partially reversed by co-treatment with the glutamine synthetase inhibitor, methionine sulphoximine. Glutamate, the precursor of glutamine, is provided by stimulated anaplerotic flux via pyruvate carboxylase and glutamate dehydrogenase activity. Thus, the glutamine increase and myo-inositol decrease observed by in vivo magnetic resonance spectroscopy on patients with hepatic encephalopathy may be due to the disturbed osmoregulation in astrocytes caused by accumulation of glutamine and the subsequent loss of organic osmolytes.

show abstract

Portal-Systemic Encephalopathy: A Disorder of Neuron-Astrocytic Metabolic Trafficking

Cited by 57 publications

References 33 publications

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Multinuclear NMR Spectroscopy Studies on NH<sub>4</sub>Cl-Induced Metabolic Alterations and Detoxification Processes in Primary Astrocytes and Glioma Cells

Contact Info

Product

Resources

About