Publicação
Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier
| dc.contributor.advisor | Brito, Maria Alexandra, 1960- | por |
| dc.contributor.advisor | Brites, Dora, 1951- | por |
| dc.contributor.author | Palmela, Inês Maria Simões, 1985- | por |
| dc.date.accessioned | 2014-01-03T16:57:04Z | |
| dc.date.available | 2014-01-03T16:57:04Z | |
| dc.date.issued | 2013 | |
| dc.description | Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2013 | por |
| dc.description.abstract | During 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. | eng |
| dc.description.provenance | Submitted by amelia Janeiro (ajaneiro@reitoria.ul.pt) on 2014-01-03T16:56:18Z No. of bitstreams: 1 ulsd067084_td_Ines_Palmela.pdf: 100824524 bytes, checksum: e650b28102257df16866d5ee063ebffa (MD5) | eng |
| dc.description.provenance | Made available in DSpace on 2014-01-03T16:57:04Z (GMT). No. of bitstreams: 1 ulsd067084_td_Ines_Palmela.pdf: 100824524 bytes, checksum: e650b28102257df16866d5ee063ebffa (MD5) | eng |
| dc.description.sponsorship | Fundação para a Ciência e a Tecnologia (FCT, SFRH/BD/61646/2009, projetos PEst-OE/SAU/UI4013/2011 e PTDC/SAU-FCF/68819/2006) | por |
| dc.identifier.tid | 101375441 | |
| dc.identifier.uri | http://hdl.handle.net/10451/9919 | |
| dc.language.iso | eng | eng |
| dc.subject | Teses de doutoramento - 2013 | por |
| dc.title | Behind bilirubin neurotoxicity: discovering what’s left at the blood-brain barrier | eng |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| rcaap.contributor.authoremail | repositorio@reitoria.ulisboa.pt | |
| rcaap.rights | embargoedAccess | eng |
| rcaap.type | doctoralThesis | eng |
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