title: Blood-brain barrier and bilirubin: clinical aspects and experimental data.
abstract: The blood-brain barrier (BBB) is a complex and dynamic structure that plays a key role in central nervous system (CNS) homeostasis. It strictly regulates the entrance of molecules into the brain parenchyma and prevents the access of neurotoxins and pathogens while promoting the efflux of several molecules. The brain microvascular endothelial cells are the anatomical basis of the BBB, which has unique characteristics such as the elaborate junctional complexes that nearly obliterate the intercellular space as well as the presence of influx and efflux transporters. Endothelial cells establish important interactions with glial cells, neurons, and perivascular pericytes as well as with the acellular components of the basement membrane, which together constitute the neurovascular unit. BBB disruption has been reported in a wide range of CNS pathologies, with an emerging role in the onset and disease progression. Accordingly, recent studies revealed vascular dysfunction in neonatal jaundice, a common pathology in the early neonatal period affecting 1/10 children presenting values of total bilirubin>17 mg/dL (291 μM). Here we summarize the clinical aspects of moderate to severe neonatal jaundice and provide a comprehensive review of the literature regarding bilirubin-induced neurotoxicity from a vascular-centered approach. The collected evidence place endothelial dysfunction and pericyte demise as key players in the disruption of CNS homeostasis, mainly in cases of lasting hyperbilirubinemia, thus pointing to novel targets to prevent neurological dysfunction due to severe neonatal jaundice.
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: abrito@ff.ulisboa.pt.
authors.forename: Maria Alexandra
authors.initials: MA
authors.lastname: Brito
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Palmela
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Filipa Lourenço
authors.initials: FL
authors.lastname: Cardoso
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Sá-Pereira
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Dora
authors.initials: D
authors.lastname: Brites
mesh_terms: D001663:Bilirubin / Q000378:metabolism*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D006932:Hyperbilirubinemia / Q000097:blood; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism / Q000473:pathology
chemical_list: D009498:Neurotoxins; D001663:Bilirubin
keywords: Blood–brain barrier; Endothelial cells; Kernicterus; Neonatal jaundice; Neurovascular unit; Pericytes