Inhibition of Glutamate Uptake by Unconjugated Bilirubin in Cultured Cortical Rat Astrocytes: Role of Concentration and pH

Silva, Rui; Mata, Lucinda R.; Gulbenkian, S.; Brito, Maria Alexandra; Tiribelli, Claudio; Brites, Dora

doi:10.1006/bbrc.1999.1646

Cited by 91 publications

(49 citation statements)

References 49 publications

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“…3a) suggests a relationship between blood parameters and brain metabolism. This interpretation would accord with an observation by Silva et al that the uptake of glutamate by cultered rat astrocytes is inhibited at pH values of 7.4 to 7.8 as compared with pH= 7.0 [23]. We conclude that our present data are best explained by the concept that the increased brain tissue Glx in ALF might represent increased glutamate concentrations, partly associated with pH decrease.…”

Section: Glutamate/glutamine (Glx)supporting

confidence: 93%

Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure

et al. 2008

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Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P<0.01; lactate + 33%, P<0.05) and higher Glx in grey matter (Glx + 125%: P< 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P<0.05), and negative correlations between grey or white matter Glx and venous pH (P<0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase).

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Section: Glutamate/glutamine (Glx)supporting

confidence: 93%

Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure

et al. 2008

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“…Moreover, UCB enhanced the effects of hypoxia in these immature neurons by facilitating glutamate-mediated apoptosis (Grojean et al, 2001). On the other hand, UCB inhibited glutamate uptake in cultured rat cortical astrocytes, which play a major role in the transport of synaptically released glutamate (Silva et al, 1999). This inhibition was directly correlated with the UCB/albumin molar ratio and was observed at a molar ratio as low as 0.8.…”

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confidence: 88%

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties

Kapitulnik¹

2004

Molecular Pharmacology

219

180

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“…3 In addition, we recently showed that UCB, at clinically relevant concentrations and short time of exposure (4 h), plays a critical role in the activation of rat-cultured astrocytes to express tumor necrosis factor-a (TNF-a) and interleukin (IL)-1b and that lipopolysaccharide accentuates these effects. 4 Exposure of rat-cultured astrocytes to UCB increases the extracellular concentration of glutamate by decreased uptake 5 and/or enhanced secretion, 4 engendering overstimulation of glutamate and N-methyl-Daspartate (NMDA) receptors (excitotoxicity). 6 It is fascinating that some papers connect neonatal hyperbilirubinemia and Gilbert's syndrome with the development of mental illness, namely schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Biological risks for neurological abnormalities associated with hyperbilirubinemia

et al. 2009

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Unconjugated bilirubin (UCB) injury to glial cells leads to the secretion of glutamate and elicits a typical inflammatory response. Release of pro-inflammatory cytokines may influence gliogenesis and neurogenesis, and lead to deficits in learning and memory. Glutamate metabolism dysregulation and overexpression of tumor necrosis factor-a (TNF-a) and interleukin (IL)-1b are consistent with schizophrenia neuropathology. Recently, an increased prevalence of schizophrenia was reported in individuals with Gilbert's syndrome and among those who have had elevated levels of UCB in the neonatal life. In this review, we explore the reactivity of astrocytes, neurons and microglia to UCB, the cascade of events implicated in the immunostimulant effects of UCB, as well as the role of each nerve cell type and maturation state in the neuropathology of UCB. Identification of the signaling events promoted by UCB will be relevant for developing novel therapies that might reduce the risk of brain injury and disabilities.

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Inhibition of Glutamate Uptake by Unconjugated Bilirubin in Cultured Cortical Rat Astrocytes: Role of Concentration and pH

Cited by 91 publications

References 49 publications

Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure

Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties

Biological risks for neurological abnormalities associated with hyperbilirubinemia

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