Evidências pré-clínicas do efeito antimaníaco de um antagonista do receptor da angiotensina

• Main Author: Gomes, Julia Ariana de Souza
• Other Authors: Gaspar, Danielle Macêdo
• Language: Portuguese
• Published: 2014
• Subjects: Transtorno Bipolar; Dextroanfetamina
• Online Access: http://www.repositorio.ufc.br/handle/riufc/7221

GOMES, Júlia Ariana de Souza. Evidências pré-clínicas do efeito antimaníaco de um antagonista do receptor da angiotensina. 2014. 95 f. Dissertação (Mestrado em Farmacologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2014. === Submitted by denise santos ([e-mail]) on 2014-02-07T13:33:49Z No. of bitstreams: 1 2014_dis_jasgomes.pdf: 1738368 bytes, checksum: 1b4031b9283720e2b14a9a818a19c976 (MD5) === Approved for entry into archive by denise santos([e-mail]) on 2014-02-07T13:34:38Z (GMT) No. of bitstreams: 1 2014_dis_jasgomes.pdf: 1738368 bytes, checksum: 1b4031b9283720e2b14a9a818a19c976 (MD5) === Made available in DSpace on 2014-02-07T13:34:38Z (GMT). No. of bitstreams: 1 2014_dis_jasgomes.pdf: 1738368 bytes, checksum: 1b4031b9283720e2b14a9a818a19c976 (MD5) Previous issue date: 2014 === The Bipolar Disorder (BD) is a highly prevalent and chronic psychiatric disorder, associated with functional disability and excessive cost to the health system. The pharmacological therapy of BD displays low efficacy due the complex and poorly understood etiology, which makes it imperative to find new therapeutic targets for this disorder. The renin-angiotensin system (RAS) has been studied concerning neurological diseases, and is currently recognized important role of angiotensin II in anxiety and mood disorders. The deregulation of SRA brain is associated with the formation of reactive oxygen species, activation of proinflammatory pathways, reduced neuroplasticity and mitochondrial dysfunction. It is noteworthy that all these events are related to the pathophysiology of BD. Thus, this study aimed to evaluate the effect of candesartan (CDS) in an animal model of mania induced by d-amphetamine (AMPH). The animals were submitted to two treatment protocols. In prevention protocol, animals received CDS (0.1; 0.3; 1 or 3 mg/kg/day), lithium (47.5 mg/kg/day) or vehicle for 14 days and between the 8th and 14th day received AMPH (2 mg/kg/day ip) or saline. In reversal protocol, was administered AMPH or saline for 14 days and between the 8th and 14th day the animals were treated with CDS, lithium or vehicle. The effect of CDS was evaluated on 14th day by exploratory behavior of animals in the open field test used for pre-clinical study of antimanic drugs. The working memory was also evaluated by Y Maze test. Neurochemical analisis of oxidative stress (TBARS and GSH), was assessed in cerebellar vérmix (CV), prefrontal cortex (PF), hippocampus (HPC) and striatum (ST). For evaluate the levels of BDNF, TNF-α e fosfo-Ser9-GSK-3β,we used CDS 0,3 and CDS 1. BDNF and fosfo-Ser9-GSK-3β was assessed only in HPC and TNF-α in HPC and CV. In both treatment protocols, there was an increase in locomotor activity in the animals that received only AMPH, which was prevented and reversed by CDS, whose results were similar to the control group and the animals that received AMPH and lithium. In the memory test, the CDS prevented and reversed the cognitive impairment caused by AMPH and only the CDS doses of 0.1 in prevention protocol and 0.3 in reversal protocol were not successful. Lithium treatment neither prevented nor reversed the cognitive impairment. The CDS increased GSH levels in HPC and CV in the prevention protocol and in PF, HPC and ST in the reversal protocol. The TBARS levels were reduced by CDS in PF, HPC and CV in the prevention protocol and in PF, HPC and ST in the reversal protocol. However, MDA level was increased by higher dose of CDS in ST in prevention protocol and by the two lower doses of CDS in CV in reversal protocol. In both treatment protocols, AMPH reduced BDNF and lithium and both doses of CDS restored the levels of this neurotrophin. In the prevention protocol, AMPH and both doses of CDS reduced the level of phospho-Ser9-GSK-3β that was significantly increased by lithium. The levels of TNF-α were increased by AMPH and reduced by lithium in HPC and VC. CDS prevented the increase of TNF-α in HPC and prevented and reversed this increase in CV. Our findings showed that CDS, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for evaluating CDS as a novel antimanic agent, however new pre-clinical studies are necessary. === O Transtorno Afetivo Bipolar (TAB) é uma doença crônica, altamente incapacitante e associada a custo excessivo aos sistemas de saúde. Atualmente, reconhece-se o papel importante da Angiotensina II em transtornos de ansiedade e humor. A desregulação do Sistema renina-angiotensina (SRA) cerebral pela ativação de receptores da angiotensina II subtipo 1 (AT1Rs) está associada à formação de espécies reativas de oxigênio, ativação de vias pró-inflamatórias, redução da neuroplasticidade e disfunção mitocondrial, estando esses eventos relacionados com a fisiopatologia do TAB. Assim, objetivou-se avaliar a ação da candesartana (CDS) em um modelo animal de mania induzido por d-anfetamina (AMPH). Utilizou-se camundongos Swiss machos (peso: 20-25g) submetidos a dois protocolos de tratamento. No protocolo de prevenção (PP), os animais receberam CDS (0,1; 0,3; 1 ou 3 mg/Kg/dia), lítio (47,5 mg/Kg/dia) ou veículo por 14 dias e entre o 8º e o 14º dia receberam AMPH (2 mg/Kg/dia i.p) ou salina. No protocolo de reversão (PR), administrou-se AMPH ou salina por 14 dias e entre o 8º e o 14º dia os animais foram tratados com CDS, lítio ou veículo. No 14º dia, os animais foram submetidos aos testes comportamentais, campo aberto e Y Maze. Foram realizadas análises neuroquímicos para avaliar o estresse oxidativo (TBARS e GSH) no vérmis cerebelar (VC), córtex pré-frontal (PF), hipocampo (HPC) e corpo estriado (CE). Além disso, foram avaliados os níveis de BDNF, TNF-α e fosfo-Ser9-GSK-3β para as doses de 0,3 e 1 mg/Kg de CDS. Os níveis de fosfo-Ser9-GSK-3β e BDNF foram avaliados apenas no HPC e os níveis de TNF-α no HPC e VC. Em ambos os protocolos de tratamento, observou-se aumento da atividade locomotora nos grupos que receberam apenas AMPH, que foi prevenida e revertida pela CDS. Os resultados obtidos nos animais tratados com CDS + AMPH foram semelhantes aos do grupo controle e dos animais que receberam Lítio + AMPH. No teste de Y maze, a CDS conseguiu prevenir e reverter o prejuízo cognitivo causado pela AMPH e apenas as doses de CDS 0,1 no PP e 0,3 no PR não tiveram efeito, assim como o tratamento com lítio em ambos os protocolos. A CDS aumentou os níveis de GSH no HPC e VC no PP e no PF, HPC e CE no PR. Os níveis de TBARS foram reduzidos pela CDS no PF, HPC e VC no PP e no PF, HPC e CE no PR. Em ambos os protocolos de tratamento, a AMPH reduziu os níveis hipocampais de BDNF e o lítio e ambas as doses de CDS avaliadas restauraram os níveis dessa neurotrofina. No PP, a AMPH e ambas as doses de CDS reduziram o nível de fosfo-Ser9-GSK-3β que foi expressivamente aumentado pelo lítio. Os níveis de TNF-α foram aumentados pela AMPH e reduzidos pelo lítio no HPC e VC. Ambas as doses de CDS avaliadas tiveram efeito na prevenção do aumento de TNF-α no HPC e preveniram e reverteram esse aumento no VC. Juntos, os dados mostraram que a CDS, semelhante ao Li, é efetiva na prevenção e reversão de alterações comportamentais e neuroquímicas induzidas pela AMPH, com exceção da fosfo-Ser9-GSK-3β, sugerindo que estudos sejam desenvolvidos para avaliação da atividade antimaníaca desse fármaco em pacientes bipolares, porém mais estudos pré-clínicos são necessários.