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Authors
Abstract(s)
O acidente vascular cerebral constitui a principal causa de morte em Portugal e de acordo com a Sociedade Portuguesa do Acidente Vascular Cerebral, Portugal é o país da Europa Ocidental com maior taxa de mortalidade, sobretudo na população com menos de 65 anos de idade. Os tratamentos existentes não são totalmente eficazes e apenas beneficiam uma pequena percentagem de doentes acarretando, na maioria das vezes, efeitos secundários graves. Assim, o desenvolvimento de novas terapias é uma necessidade obrigatória. Esta doença desencadeia uma série de alterações celulares e moleculares que comprometem a viabilidade do tecido nervoso. Neste contexto, a resposta inflamatória desencadeada pela microglia, células do sistema imune inato do Sistema Nervoso Central, dificulta a reparação neurovascular. Após um acidente vascular cerebral, a vasculatura é lesada levando a um comprometimento do suporte trófico de todos os tecidos que irriga, assim como no número de novos neurónios que acorre à área de lesão. Assim, pretendemos acionar mecanismos que modulem a resposta anti-inflamatória da microglia e potenciem a reparação neurovascular. Para tal, propomos o uso do ácido retinóico (um derivado da vitamina A, anti-inflamatório e pro-angiogénico) como agente terapêutico. Para contornar a baixa solubilidade e rápida degradação desta molécula, recorremos ao uso de nanopartículas poliméricas carregadas com ácido retinóico. Após a concretização deste projeto, concluímos que a formulação 1) induz um efeito anti-inflamatório na microglia num contexto isquémico; 2) modula o secretoma das células endoteliais isquémicas de forma a promover uma reposição dos níveis de óxido nítrico e a produzir sinais anti-inflamatórios pela microglia; 3) promove a sobrevivência e reparação neurovascular num contexto inflamatório após a injeção intravenosa e em condições isquémicas. Assim, as nanopartículas poliméricas carregadas com ácido retinóico demostram ser um agente com grande potencial terapêutico para administração intravenosa do acidente vascular cerebral.
Stroke constitutes the leading cause of death in Portugal and according to the Portuguese Stroke Society, Portugal is the Western European country with the highest mortality rate, especially in the population under 65 years old. As the treatments available are not fully effective and only benefit a small percentage of patients, leading most often to serious side effects, the development of new therapies is an emerging need. This disease triggers a series of cellular and molecular changes that compromise the viability of the nervous tissue. In this context, the inflammatory response triggered by microglia, the innate immune system cells of the Central Nervous System, accentuates neurovascular damage. Stroke-induced vascular deregulation and/or injury compromises trophic and migratory support of new neurons to the lesion area affecting the final outcome. Accordingly, our goal is to modulate these mechanisms to suppress the inflammatory response and to potentiate neurovascular repair, using retinoic acid (an anti-inflammatory and pro-angiogenic vitamin A derivative) as the therapeutic agent. To bypass the low solubility and the fast degradation of this molecule, we propose the use of retinoic acid-loaded polymeric nanoparticles. In sum, we concluded that our formulation 1) induces an anti-inflammatory phenotype on microglia cells in an ischemic context; 2) modulates the secretome of ischemic endothelial cells towards normalized nitric oxide production and anti-inflammatory cues for microglia cells; 3) promotes survival and neurovascular repair in a suitable inflammatory environment following intravenous injection and ischemia. Thus, this formulation has shown great therapeutic potential for the intravenous treatment of stroke.
Stroke constitutes the leading cause of death in Portugal and according to the Portuguese Stroke Society, Portugal is the Western European country with the highest mortality rate, especially in the population under 65 years old. As the treatments available are not fully effective and only benefit a small percentage of patients, leading most often to serious side effects, the development of new therapies is an emerging need. This disease triggers a series of cellular and molecular changes that compromise the viability of the nervous tissue. In this context, the inflammatory response triggered by microglia, the innate immune system cells of the Central Nervous System, accentuates neurovascular damage. Stroke-induced vascular deregulation and/or injury compromises trophic and migratory support of new neurons to the lesion area affecting the final outcome. Accordingly, our goal is to modulate these mechanisms to suppress the inflammatory response and to potentiate neurovascular repair, using retinoic acid (an anti-inflammatory and pro-angiogenic vitamin A derivative) as the therapeutic agent. To bypass the low solubility and the fast degradation of this molecule, we propose the use of retinoic acid-loaded polymeric nanoparticles. In sum, we concluded that our formulation 1) induces an anti-inflammatory phenotype on microglia cells in an ischemic context; 2) modulates the secretome of ischemic endothelial cells towards normalized nitric oxide production and anti-inflammatory cues for microglia cells; 3) promotes survival and neurovascular repair in a suitable inflammatory environment following intravenous injection and ischemia. Thus, this formulation has shown great therapeutic potential for the intravenous treatment of stroke.
Description
Keywords
Acidente Vascular Cerebral Ácido Retinóico Nanomateriais Neuroinflamação Sistema Vascular