Evaluation of dopaminergic degeneration influence on endothelial activity in experimental models of Parkinson's Disease

• Autor(a) principal: Lindeza, Patrícia Vanessa Almeida
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/6146
• topic: Barreira Hemato-Encefálica; Doença de Parkinson; Hmgb1; Modelos Animais; Neurónios Dopaminérgicos; Paraquato; Rage; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

Parkinson’s disease (PD) is a common neurodegenerative disorder with no known cure. The animal models, in particular the PD models, are important tools in experimental medical science to better understand the mechanisms involved in disease pathogenesis. The ideal animal model for PD should recapitulate most, if not all, features of the human disease. Actual PD animal models available do not show prominent alpha-synucleinopathy, an hallmark of the disease, leading to their restrictive application to undisclosed important molecular mechanisms responsible for PD development. In this way, the implementation of a new model that mimic PD in a more consistent way will be an important step to improve future investigations. In this work, we developed a novel paraquat (PQ)-based chronic PD model by using osmotic minipumps to assure the continuous administration of low doses of PQ for a longer period. Besides the fact that the exposure paradigm mimics in a closer way what happen in humans, this model also reproduces several key characteristics of the human PD, including the important alpha-synucleinopathy. Recent studies have implicated the Blood-Brain Barrier (BBB) as one of the underexplored brain structures in PD. Clinical evidences indicate that BBB dysfunctions are associated with a number of serious CNS diseases. HMGB1 has been shown to be a long-searched-for nuclear danger signal passively released by necrotic cells inducing inflammation. Its receptor, RAGE, is expressed in various cells, including endothelial cells that are largely present in BBB being involved in chronic inflammation and cell proliferation and migration. Despite the importance of this receptor in several diseases such as multiple sclerosis, stroke, brain tumors, AD and cancer, there is no consistent information about this receptor in Parkinson's disease neuroinflammation. In previous studies, another RAGE ligand (S100B) have been reported to be overexpressed in PD patients, despite there are evidences that neuroinflammation associated with PD can compromise the BBB. In this way, it will be of great importance to analyse the expression levels of HMGB1 and RAGE within PD experimental models. Our results revealed an increase of HMGB1 and RAGE expression levels with more significance in vivo models, specifically in PQ and 6-hydroxidopamine models. In this way, the obtained results indicates that a deeper study of the role of both HMGB1 and RAGE in PD will be of great interest to understand they role in PD neuroinflammation and to know if they targeting may serve as a neuroprotective approaches against the development and/or progression of PD.