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Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier

Bibliographic Details
Main Author: Palmela, Inês Maria Simões, 1985-
Publication Date: 2013
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/9919
Summary: Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2013
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spelling Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrierTeses de doutoramento - 2013Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2013During neonatal life, elevation of unconjugated bilirubin (UCB) levels may lead to minor neurological dysfunction or even to bilirubin encephalopathy (kernicterus). The pathogenesis of this condition involves UCB passage across the blood-brain barrier (BBB), but it is still unknown the role of this barrier in the consequent brain injury. Thus, this thesis intended to investigate the response of human brain microvascular endothelial cells (HBMEC), a simplified in vitro model of the BBB, to UCB, to evaluate the modulation of these effects by therapeutic molecules, and to dissect the neuro-glialvascular alterations in brain parenchyma of neonatal kernicterus cases.First, we observed that HBMEC incubation with UCB induced cell death,cytokine release and oxidative stress. As some of the molecules that the HBMEC produced are known modulators of permeability and angiogenesis, we continued our studies with the evaluation of barrier integrity. Our second study showed that prolonged exposure to high concentrations of UCB caused monolayer fragility and compromised barrier integrity. To complement these studies, we investigated the action of the neuroprotective bile acids, ursodeoxycholic acid (UDCA) and glycoursodeoxycholic acid (GUDCA) against UCB toxicity. The bile acids showed optimal protective abilities in distinct parameters: GUDCA was effective in preventing cell death, while UDCA reduced the production of angiogenic-related molecules and prevented the elevation of permeability. Importantly, the bile acids efficiency was demonstrated in a broad window of opportunity, with both protective and recovery properties. Next, we continued our work by analysing brain regions with great susceptibility to bilirubin, as the cerebellum, hippocampus and basal ganglia, which showed marked neuronal loss. Additionally, the results revealed new players in the neuropathology of kernicterus, including increased vascularization and dysfunction in several BBB components, as astrocytes, pericytes and basement membrane.In conclusion, high levels of UCB compromise endothelial integrity, mainly after prolonged exposure, ultimately leading to BBB breakdown and enhanced UCB passage into the brain. Additionally, our data shows the potential of UDCA and GUDCA as preventive, but also restorative therapeutic molecules against UCB-injury. Moreover, evaluation of kernicterus cases suggests a link between region-specific susceptibility and marked vascular dysfunction. These findings contribute to a better understanding of the neurotoxic steps involved in the irreversible brain damage cause by severe jaundice.Fundação para a Ciência e a Tecnologia (FCT, SFRH/BD/61646/2009, projetos PEst-OE/SAU/UI4013/2011 e PTDC/SAU-FCF/68819/2006)Brito, Maria Alexandra, 1960-Brites, Dora, 1951-Repositório da Universidade de LisboaPalmela, Inês Maria Simões, 1985-2014-01-03T16:57:04Z20132013-01-01T00:00:00Zdoctoral thesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10451/9919TID:101375441enginfo:eu-repo/semantics/embargoedAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T13:03:42Zoai:repositorio.ulisboa.pt:10451/9919Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T02:34:03.915360Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
title Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
spellingShingle Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
Palmela, Inês Maria Simões, 1985-
Teses de doutoramento - 2013
title_short Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
title_full Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
title_fullStr Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
title_full_unstemmed Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
title_sort Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
author Palmela, Inês Maria Simões, 1985-
author_facet Palmela, Inês Maria Simões, 1985-
author_role author
dc.contributor.none.fl_str_mv Brito, Maria Alexandra, 1960-
Brites, Dora, 1951-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Palmela, Inês Maria Simões, 1985-
dc.subject.por.fl_str_mv Teses de doutoramento - 2013
topic Teses de doutoramento - 2013
description Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2013
publishDate 2013
dc.date.none.fl_str_mv 2013
2013-01-01T00:00:00Z
2014-01-03T16:57:04Z
dc.type.driver.fl_str_mv doctoral thesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/9919
TID:101375441
url http://hdl.handle.net/10451/9919
identifier_str_mv TID:101375441
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/embargoedAccess
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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