Bilirubin does not modulate ionotropic glutamate receptors or glutamate transporters

Warr, Orpheus; Mort, D.; Attwell, David

doi:10.1016/s0006-8993(00)02676-7

Cited by 22 publications

(12 citation statements)

References 22 publications

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“…Additionally, Oakden et al [58] have identified an increase in glutamate and glutamine in the basal ganglia of children with kernicterus using 1 H MR spectroscopy. More consistent with our results of a non-NMDA dependent mechanism is the report by Warr et al [23] , which utilized patch clamp electrophysiological methods of hippocampal slices from 12-day-old rat pups and demonstrated no changes in the NMDA or AMPA induced currents with the addition of bilirubin. Thus, we believe our in vivo demonstration of lack of MK-801 neuroprotection of auditory dysfunction complements Warr's electrophysiology data and supports the conclusion that bilirubin toxicity is not mediated through NMDA receptor activation.…”

Section: Discussionsupporting

confidence: 93%

“…There is evidence both for [17-19, 21, 22, 47] and against [23] the hypothesis that bilirubin causes brain damage through an NMDA-dependent mechanism. In contrast to our results, Grojean et al [18] found that 0.5 M bilirubin (in serum-free medium) triggered delayed cell death and a decrease in MTT reduction at 96 h in primary forebrain neuronal cultures from 14-dayold embryos cultured for 6 days in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, intracerebral injection of NMDA in jaundiced Gunn rat pups produced more gross histological damage than in nonjaundiced littermates [17] . However, more direct in vitro studies have produced conflicting results on the role of the NMDA channel in bilirubin neurotoxicity [18][19][20][21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

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NMDA Channel Antagonist MK-801 Does Not Protect against Bilirubin Neurotoxicity

Shapiro

Sombati²,

Geiger³

et al. 2007

Neonatology

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Background: Bilirubin encephalopathy or kernicterus is a potentially serious complication of neonatal hyperbilirubinemia. The mechanism of bilirubin-induced neurotoxicity is not known. Many neurological insults are mediated through NMDA receptor activation. Objective: We assessed the effect of the NMDA channel antagonist, MK-801 on bilirubin neurotoxicity in vivo and in vitro. Methods: Bilirubin toxic ity in vitro was assessed using trypan blue staining. Sulfadimethoxine injected (i.p.) jaundiced Gunn rat pups ex hibit many neurological sequelae observed in human hyperbilirubinemia. Brainstem auditory-evoked potentials (BAEPs), a noninvasive sensitive tool to assess auditory dysfunction due to bilirubin neurotoxicity, were used to assess neuroprotection with MK-801 (i.p.) in vivo. Results: In primary cultures of hippocampal neurons, 20 min exposure to 64:32 µM bilirubin:human serum albumin reduced the cell viability by approximately 50% ten hours later. MK-801 treatment did not protect the cells. MK-801 pretreatment doses ranging from 0.1–4.0 mg/kg did not protect against BAEP abnormalities in Gunn rat pups 6 h after sulfadimethoxine injection. Conclusion: Our findings suggest that bilirubin neurotoxicity is not mediated through NMDA receptor activation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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NMDA Channel Antagonist MK-801 Does Not Protect against Bilirubin Neurotoxicity

Shapiro

Sombati²,

Geiger³

et al. 2007

Neonatology

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“…NMDA injections into the brain caused greater damage in hyperbilirubinemic Gunn rats than in nonjaundiced controls, and concurrent treatment with MK-801 reduced this injury (5). Conflicting data exist as to whether this increased neuronal damage is due to enhanced sensitivity of the NMDA receptor to glutamate in the presence of bilirubin (4,20). In the present study, MK-801 protected against UCB-induced cell death by reducing the proportion of cells displaying condensed nuclei, but had no impact on the …”

Section: Discussioncontrasting

confidence: 46%

Synergistic Protection of a General Caspase Inhibitor and MK-801 in Bilirubin-Induced Cell Death in Human NT2-N Neurons

et al. 2006

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Unconjugated bilirubin (UCB) induces both apoptosis and necrosis in neurons. To investigate the role of caspases and excitotoxicity in UCB-induced cell death, we exposed NT2-N neurons to 5 M UCB (a concentration known to induce apoptosis) or 2 M staurosporine (positive apoptosis control) and investigated the effects of treatments with the specific caspase-3 inhibitor, zDEVD.FMK (20 and 100 M), or the general caspase inhibitor, zVAD.FMK (20 and 100 M), and/or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (10 M) during a 24-or 48-h exposure. UCB increased caspase-3 activity 2.3-fold after 6 h. Despite this, treatment with zDEVD.FMK did not prevent cell death. zVAD.FMK (100 M only) reduced apoptotic morphologies induced by UCB after 48 h, however, this effect was not reflected in MTT assays. MK-801 attenuated UCB-induced cell death after 24 h, but not significantly after 48 h. Similar effects were seen in the MTT assay. Combined treatment with MK-801 and zVAD.FMK synergistically reduced apoptotic morphologies after 24 and 48 h. MTT assays showed comparable effects after 24 h but did not show significant differences after 48 h. We conclude that NMDA receptormediated pathways and caspase-mediated pathways are involved in UCB-induced cell death in human NT2-N neurons. Concomitant inhibition of both pathways results in synergistic protection.

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“…There are studies that argue for [51][52][53] and against [54,55] the hypothesis that UCB causes brain damage through a similar mechanism. Histologically, the brain of the jaundiced Gunn rat shows both eosinophilic neurons consistent with necrosis, and condensation and clumping of nuclear chromatin consistent with apoptotic cell death [52]; evidence that this injury is caused by an NDMA receptormediated excitoxic mechanism needs to be confirmed with quantitative analyses.…”

Section: Redox Regulation Of Cellular Functions: New Perspectives Formentioning

confidence: 99%

The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1–2 October, 2004

Tiribelli

Ostrow

2005

Journal of Hepatology

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Bilirubin does not modulate ionotropic glutamate receptors or glutamate transporters

Cited by 22 publications

References 22 publications

NMDA Channel Antagonist MK-801 Does Not Protect against Bilirubin Neurotoxicity

NMDA Channel Antagonist MK-801 Does Not Protect against Bilirubin Neurotoxicity

Synergistic Protection of a General Caspase Inhibitor and MK-801 in Bilirubin-Induced Cell Death in Human NT2-N Neurons

The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1–2 October, 2004

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