Bilirubin Induces Apoptosis via Activation of NMDA Receptors in Developing Rat Brain Neurons

Grojean, Stéphanie; Koziel, Violette; Vert, P; Daval, Jean‐Luc

doi:10.1006/exnr.2000.7518

Cited by 124 publications

(82 citation statements)

References 51 publications

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“…8,3,15 Bilirubin is a known neuronal toxin, and it may play a role in the etiology of AN. [16][17][18][19] In a recent study, Berg et al 12 reported an association between AN and elevated peak total bilirubin levels. However, total bilirubin levels are difficult to interpret in the absence of additional metabolic and nutritional information, especially since bilirubin bound to albumin does not cross the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 98%

Extremely low birth weight infants are at high risk for auditory neuropathy

et al. 2007

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Auditory neuropathy (AN) is a condition in which transmission of sound to the brain is abnormal. This is reflected as an electrophysiologic profile of normal otoacoustic emissions (OAE), with abnormal auditory brainstem evoked responses (ABR). Functionally speech perception is impaired and management strategies remain controversial. AN can be missed if high-risk newborns are screened for hearing loss with only OAE testing. The rate of sensorineural hearing loss (SNHL) in high-risk nursery infants is 10 times greater compared with normal term newborns. Therefore, we hypothesize that infants from the neonatal intensive care unit (NICU) are at significantly higher risk for AN than normal term infants.Objective: The objective of this study is to establish a prevalence rate and characterize risk factors for NICU graduates who demonstrate the AN electrophysiologic profile.Study Design: This retrospective study examined infants admitted to the NICU at Kapi'olani Medical Center for Women and Children in Honolulu, HI from 1999 through 2003. Infants were screened with automated ABR. Diagnostic testing and OAE were performed before discharge if the ABR was abnormal. Hospital courses of 24 AN, 71 SNHL and 95 gestational age (GA)-matched control infants with normal hearing were reviewed.Result: With a SNHL prevalence of 16.7/1000, the rate for AN was 5.6/1000 NICU infants. Compared to infants with SNHL, infants with AN were significantly younger (GA 28.3±4.8 AN vs 32.9±5.2 weeks SNHL, P<0.0001) and smaller (BW 1318±894 AN vs 1968±1006 g SNHL).Nearly two-thirds of the AN infants were ELBW and had significantly longer hospital stays compared to SNHL infants of the same birth weight group. Exposure to furosemide, aminoglycosides, vancomycin or dexamethasone was associated with increased AN but not SNHL. Peak bilirubin level correlated with SNHL but not AN.Conclusion: Low birth weight NICU infants are at significant risk for AN. ELBW infants are at significantly higher risk for both AN and SNHL.Infants admitted to the NICU should be routinely screened by automated ABR and if abnormal, further evaluation should be started before hospital discharge. Early identification of AN will result in better understanding of this disorder and lead to the development of appropriate intervention strategies.

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Section: Discussionmentioning

confidence: 98%

Extremely low birth weight infants are at high risk for auditory neuropathy

et al. 2007

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“…Finally, the decreased neurotoxic effects of UCB with cell age in culture along with increased responsiveness of mitochondria may also indicate that bilirubin-induced cell injury is not solely mediated through mitochondrial disturbances. In this regard, it has recently been shown that bilirubin induces apoptosis via activation of Nmethyl-D-aspartate receptors and inhibition of protein kinase C activity (30). Mitochondria may, nevertheless, be a common target for different apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

Aging Confers Different Sensitivity to the Neurotoxic Properties of Unconjugated Bilirubin

et al. 2002

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“…These investigators performed the majority of analyses of bilirubin-induced apoptosis at a bilirubin: albumin molar ratio of 3, 64 using concentrations at which bilirubin would be anticipated to precipitate from solution. 20 Moreover, as opposed to bilirubin-mediated neuronal cell death, which is triggered by stimulation of the NMDA receptor 66 and prevented by NMDA receptor antagonists, 22 both glutamate and NMDA inhibitors reduce the viability of HT29 adenocarcinoma cells. 67 These disparities in the cellular response may be a result of nonphysiologic concentrations of bilirubin utilized or, alternatively, may reflect distinct mechanisms of bilirubin action in different cell lines.…”

Section: Effect Of Bilirubin On the Permeability Of Isolated Mitochonmentioning

confidence: 99%

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

Keshavan¹,

Schwemberger²,

Smith³

et al. 2004

Intl Journal of Cancer

114

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Bilirubin is the principal end product of heme degradation. Prompted by epidemiologic analyses demonstrating an inverse correlation between serum bilirubin levels and cancer mortality, we examined the effect(s) of bilirubin on the growth and survival of colon adenocarcinoma cells. Adenocarcinoma cell monolayers were treated with bilirubin over a range of bilirubin:BSA molar ratios (0 -0.6), and viability was assessed colorimetrically. Apoptosis was characterized by TUNEL assay, annexin V staining and caspase-3 activation. The mechanism(s) by which bilirubin induces apoptosis was investigated by Western blotting for cytochrome c release, assaying for caspase-8 and caspase-9 activation and for mitochondrial depolarization by JC-1 staining. The direct effect of bilirubin on the membrane potential of isolated mitochondria was evaluated using light-scattering and fluorescence techniques. Bilirubin decreased the viability of all colon cancer cell lines tested in a dose-dependent manner. Cells exhibited substantial apoptosis when exposed to bilirubin concentrations ranging 0 -50 M, as demonstrated by an 8-to 10-fold increase in TUNEL and annexin V staining and in caspase-3 activity. Bilirubin treatment evokes specific activation of caspase-9, enhances cytochrome c release into the cytoplasm and triggers the mitochondrial permeability transition in colon cancer monolayers. Additionally, bilirubin directly induces the depolarization of isolated rat liver mitochondria, an effect that is not inhibited by cyclosporin A. Bilirubin stimulates apoptosis of colon adenocarcinoma cells in vitro through activation of the mitochondrial pathway, apparently by directly dissipating mitochondrial membrane potential. As this effect is triggered at concentrations normally present in the intestinal lumen, we postulate a physiologic role for bilirubin in modulating colon tumorigenesis.

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Bilirubin Induces Apoptosis via Activation of NMDA Receptors in Developing Rat Brain Neurons

Cited by 124 publications

References 51 publications

Extremely low birth weight infants are at high risk for auditory neuropathy

Extremely low birth weight infants are at high risk for auditory neuropathy

Aging Confers Different Sensitivity to the Neurotoxic Properties of Unconjugated Bilirubin

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

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