Modulation of bilirubin neurotoxicity by the Abcb1 transporter in the Ugt1-/- lethal mouse model of neonatal hyperbilirubinemia
| Autor: | Claudio Tiribelli, Jana Jašprová, Jaroslav Zelenka, Libor Vítek, Luka Bočkor, Andrés F. Muro, Alessandra Iaconcig, Giulia Bortolussi, Simone Vodret |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Neurotoxicity Syndrome Bilirubin Cell Survival Central nervous system Brain damage Biology Pharmacology 03 medical and health sciences chemistry.chemical_compound bilirubin neurotoxicity syndromes hyperbilirubinemia neonatal jaundice membrane transport proteins plasma brain cerebellum mice p-glycoprotein Mice 0302 clinical medicine Cerebellum Genetics medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Glucuronosyltransferase Molecular Biology hyperbilirubinemia bilirubin neurotoxicity Ugt1a1 Abcb1 Genetics (clinical) Mice Knockout Neurotoxicity General Medicine Jaundice medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Animals Newborn Toxicity Kernicterus Female Neurotoxicity Syndromes medicine.symptom Hyperbilirubinemia Neonatal Multidrug Resistance-Associated Proteins 030217 neurology & neurosurgery |
| Zdroj: | Human molecular genetics. 26(1) |
| ISSN: | 1460-2083 |
| Popis: | Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin- induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown. To this end, we mated Abcb1a/b-/- and Abcc1-/- strains with Ugt1-/- mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1-/- mice survived after temporary phototherapy, all Abcb1a/b-/-/Ugt1-/- mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important. In the cerebellum of Ugt1-/- mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response. We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity. |
| Databáze: | OpenAIRE |
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