Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

Gazzin, Silvia; Zelenka, Jaroslav; Zdrahalova, Lucie; Koníčková, Renata; Zabetta, Carlos Coda; Giraudi, Pablo J.; Berengeno, Andrea L.; Raseni, Alan; Robert, María Celeste; Vı́tek, Libor; Tiribelli, Claudio

doi:10.1038/pr.2012.23

Cited by 47 publications

(61 citation statements)

References 29 publications

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“…This finding is in line with what has been reported in animal models. In both Gunn rats and UGT−/− mice, cerebellar damage took at least 7–9 days to become significant and was not detectable at early post-natal ages, despite the presence of hyperbilirubinemia early after birth34364041424344. Also in line with this hypothesis is the observation that 4 days of exposure to 140-nM Bf increased LDH release (>2.0-fold) in our Cll OBCs (data not shown).…”

Section: Discussionsupporting

confidence: 75%

“…Cerebellar hypoplasia due to bilirubin toxicity is a landmark finding of animal models of hyperbilirubinemia34364041424344 and is reported in pre-term babies4546. In our model, we found regions of the brain susceptible to an acute exposure (24 hrs) to UCB (Hip, IC) and others that are not.…”

Section: Discussionmentioning

confidence: 62%

“…After 6 days in vitro , slices were challenged for 24 hrs with different bilirubin concentrations based on our experience in vitro 314347 and in the range of the in vivo brain Bf 50. The concentration of UCB dissolved in DMSO required to reach the desired Bf concentrations in the OBC medium was quantified according to Roca et al 51…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment

Ben

Bottin

Zanconati

et al. 2017

Sci Rep

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The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2–13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 62%

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Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment

Ben

Bottin

Zanconati

et al. 2017

Sci Rep

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“…Antioxidative properties of BR have been reported at low concentrations ranging from 0.01 -10 µM (Stocker et al, 1987;Neuzil and Stocker, 1994;Dailly et al, 1998;Hatfield and Barclay, 2004). The antioxidative property of BR has been shown to be beneficial in protection against a various disease states including vascular, cardiovascular, and neural diseases (Doré et al, 1999;Ollinger et al, 2005;Gazzin et al, 2012). Furthermore BR has been also implicated in hepatic protection against bile acid-induced apoptosis in rat hepatocytes, and hyperoxia in neonate Gunn rats (Dennery et al, 1995;Granato et al, 2003).…”

Section: Dual Characteristics Of Bilirubin (Br)mentioning

confidence: 99%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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Murine cytochrome P450 2A5 (CYP2A5) is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins. It has been reported that CYP2A5 is upregulated following exposure to chemical hepatotoxins and during pathophysiological conditions in which the levels of most Cytochrome P450s are either unchanged or down-regulated. Recently bilirubin has been identified as the first endogenous substrate for CYP2A5 and it has been suggested that CYP2A5 plays a major role in bilirubin clearance as an alternative mechanism to BR conjugation by UGT1A1. This study investigated the mechanisms of gene regulation and cytoprotective role of CYP2A5 in response to bilirubin treatment in liver. Our results demonstrate that bilirubin induces CYP2A5 expression at the mRNA and protein levels by increasing CYP2A5 transcription via a mechanism that involves Nrf2 activation. Furthermore, our results suggest that induced CYP2A5 plays a cytoprotective role against bilirubin toxicity by directly lowering the cellular levels of bilirubin and by inhibiting caspase-3 activation.iii ACKNOWLEDGEMENTS

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“…However, Gazzin et al [23] have shown distinct, transient up-regulation of P450 1a1, 1a2, and 2a3 in different regions of the brain after exposure to bilirubin. Furthermore, there were regional differences both in magnitude and timing of the responses, with cerebral cortex and superior colliculae showing a much higher and faster response within the first hour, whereas cerebellum and inferior colliculae evinced a much slower and lower response, peaking at about 24 h. These findings seem to support the idea that there is a protective response to an increase in bilirubin levels, through the upregulation of several enzymes.…”

Section: Discussionmentioning

confidence: 96%

Metyrapone, an inhibitor of cytochrome oxidases, does not affect viability in a neuroblastoma cell model of bilirubin toxicity

Leerberg

Alme

Hansen

2014

Molecular Genetics and Metabolism Reports

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BackgroundUnconjugated hyperbilirubinemia may cause brain damage in infants, and globally remains a source of neonatal morbidity and mortality. A significant inter-individual variability in vulnerability to bilirubin toxicity remains largely unexplained. An enzyme located in mitochondria oxidizes bilirubin. We hypothesized that inhibiting bilirubin oxidation in human neuronal cell cultures exposed to bilirubin would increase cell death.MethodsThe ability of mitochondrial membranes from CHP-212 human neuroblastoma cells to oxidize bilirubin was verified by spectrophotometry. Intact cells in culture were exposed to bilirubin (75 μM) with or without metyrapone (250 μM) for 24 h, stained with Annexin-V and Propidium iodide and analyzed for apoptosis and necrosis by flow cytometry.ResultsBilirubin caused a significant reduction of viability, from 84 ± 2.0% (mean ± SEM) vs 67 ± 2.7% (p < 0.05), but adding metyrapone to the bilirubin-exposed cells did not further impact cell viability. Metyrapone alone did not influence cell viability.ConclusionHerein we have shown that metyrapone does not increase cell death in neuroblastoma cells in culture exposed to bilirubin. Our results question the relationship between the oxidative mechanism evaluated by spectrophotometry and cell viability. Our findings add to the discussion on whether bilirubin oxidation represents a potentially important protective mechanism in neurons challenged by hyperbilirubinemia.

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Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

Cited by 47 publications

References 29 publications

Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment

Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Metyrapone, an inhibitor of cytochrome oxidases, does not affect viability in a neuroblastoma cell model of bilirubin toxicity

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