Efeito da estabilização de mastócitos no desenvolvimento da encefalomielite autoimune experimental
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Data
2017-06-08
Autores
Pinke, Karen Henriette [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A Esclerose múltipla é uma doença autoimune degenerativa que acomete jovens adultos, causando danos neuroaxonais e áreas de desmielinização no sistema nervoso central (SNC) devido a uma resposta autoimune mediada por linfócitos Th1, Th17 e T citotóxicos. A encefalomielite autoimune experimental (EAE) constitui seu principal modelo de estudo e mastócitos parecem contribuir para os processos inflamatórios envolvidos na patogênese da EM/EAE. Seguindo este raciocínio, substâncias estabilizadoras de mastócitos, como o fumarato de cetotifeno, poderiam afetar o desenvolvimento destas doenças através do bloqueio dos processos de exocitose e desgranulação. O objetivo principal deste trabalho foi avaliar o efeito desta droga no desenvolvimento da EAE. Para isto, camundongos C57BL/6 fêmeas submetidas à indução da EAE através da imunização com MOG/CFA e injeção de toxina pertussis, foram tratados com fumarato de cetotifeno (0,4 mg/kg via intraperitoneal) durante 11 dias, a partir do 7º dia após a indução. O efeito do tratamento no desenvolvimento clínico da EAE foi determinado pela avaliação de peso corporal e escore clínico. Posteriormente, parâmetros histopatológicos e imunológicos associados à doença, bem como a quebra da função da barreira hematoencefálica (BHE) foram avaliados. As comparações dos valores de incidência, escores clínicos diários e máximos, e de variação de peso corpóreo revelaram que o tratamento com cetotifeno reduziu a incidência e a gravidade da EAE. Este efeito protetor determinado pelo cetotifeno foi associado com a normalização da função da BHE e consequente ausência ou redução da infiltração de linfócitos no SNC, e ativação reduzida de micróglia. Também se verificou menor expressão gênica de quimase-1, mMCP-4 e carboxipeptidase-1 no SNC e grande ativação da resposta imune periférica em amostras de linfonodos e baço dos animais imunizados e tratados com cetotifeno. Considerando os resultados obtidos, concluiu-se que o tratamento com fumarato de cetotifeno impede o desenvolvimento clínico da EAE por mecanismos que envolvem a manutenção da função da BHE e consequente bloqueio da infiltração de linfócitos no SNC.
Multiple sclerosis is one of the most prevalent neurological human diseases. It triggers axonal damage and demyelinated areas in central nervous system (CNS) by an autoimmune response mediated by Th1, Th17 and T cytotoxic lymphocytes. Experimental autoimmune encephalomyelitis (EAE) is the most employed model of study this disease and mast cells appear to contribute to MS- and EAE- underlying immunopathogenesis. In this scenario, mast cell stabilizer drugs, such as ketotifen fumarate, could affect the development of these diseases by the blockage of exocytosis and degranulation. The aim of this study was to evaluate the effect of this drug on the development of EAE. For this, MOG/CFA-immunized female C57BL/6 mice were treated with ketotifen fumarate. The effect of treatment was determined by body weight loss and clinical score. Subsequently, EAE-associated histopathological and immunological parameters, as well as breakdown of blood-brain and blood-spinal cord barrier were analyzed. Comparisons about incidence values, daily and maximum clinical scores, and body weight loss revealed that ketotifen-treatment reduced the EAE-incidence and -severity. This protection was associated with the restoration of blood-spinal cord barrier function, absence or reduction of SNC lymphocytic infiltration and reduced microglial activation. Lower chymase-1, mMCP-4 and carboxypeptidase-1 gene expressions were also detected in the CNS, as well as higher activation of peripheral immune response in lymph node and splenic samples from immunized mice treated with ketotifen. Considering these results, it was concluded that the treatment with ketotifen fumarate prevents the clinical development of EAE by mechanisms related to maintenance of blood-spinal cord barrier function and consequent blockage of CNS inflammatory infiltrate.
Multiple sclerosis is one of the most prevalent neurological human diseases. It triggers axonal damage and demyelinated areas in central nervous system (CNS) by an autoimmune response mediated by Th1, Th17 and T cytotoxic lymphocytes. Experimental autoimmune encephalomyelitis (EAE) is the most employed model of study this disease and mast cells appear to contribute to MS- and EAE- underlying immunopathogenesis. In this scenario, mast cell stabilizer drugs, such as ketotifen fumarate, could affect the development of these diseases by the blockage of exocytosis and degranulation. The aim of this study was to evaluate the effect of this drug on the development of EAE. For this, MOG/CFA-immunized female C57BL/6 mice were treated with ketotifen fumarate. The effect of treatment was determined by body weight loss and clinical score. Subsequently, EAE-associated histopathological and immunological parameters, as well as breakdown of blood-brain and blood-spinal cord barrier were analyzed. Comparisons about incidence values, daily and maximum clinical scores, and body weight loss revealed that ketotifen-treatment reduced the EAE-incidence and -severity. This protection was associated with the restoration of blood-spinal cord barrier function, absence or reduction of SNC lymphocytic infiltration and reduced microglial activation. Lower chymase-1, mMCP-4 and carboxypeptidase-1 gene expressions were also detected in the CNS, as well as higher activation of peripheral immune response in lymph node and splenic samples from immunized mice treated with ketotifen. Considering these results, it was concluded that the treatment with ketotifen fumarate prevents the clinical development of EAE by mechanisms related to maintenance of blood-spinal cord barrier function and consequent blockage of CNS inflammatory infiltrate.
Descrição
Palavras-chave
Esclerose múltipla, Encefalomielite autoimune experimental, Fumarato de cetotifeno, Mastócitos, Multiple sclerosis, Experimental autoimmune encephalomyelitis, Ketotifen fumarate, Mast cells