Potencial terapêutico de cisteína selenizada em modelo experimental de esclerose múltipla
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2019-02-22
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Universidade Estadual Paulista (Unesp)
Resumo
A esclerose múltipla (EM) é uma doença inflamatória crônica e desmielinizante do sistema nervoso central (SNC). A imunopatogênese da EM envolve linfócitos Th1, Th17 e Tc autorreativos e ativação de macrófagos e microglia, os quais liberam vários mediadores pró-inflamatórios e radicais livres. Não há cura para a EM e as terapias disponíveis desencadeiam efeitos colaterais. Neste contexto, testamos o potencial terapêutico da cisteína selenizada (CS), um produto em desenvolvimento pela empresa Biorigin, no controle da encefalomielite autoimune experimental (EAE). O potencial profilático/terapêutico foi testado por administração de CS durante 30 dias (14 dias antes seguido de 16 dias pós-indução da EAE) e o potencial terapêutico por administração da CS a partir de 1 ou 7 dias após a indução da doença. Os 3 procedimentos reduziram escore clínico e incidência da EAE. A estratégia profilática/terapêutica reduziu discretamente a expressão de componentes do inflamassoma NLRP3 e o percentual de macrófagos e microglia ativada no SNC. As duas estratégias terapêuticas determinaram redução significativa no escore clínico, no percentual de macrófagos e microglia ativada e na expressão de MHCII por estas células. A terapia com CS também reduziu a ativação do inflamassoma NLRP3 e a expressão de mRNA para iNOS e CX3CR1.A redução na percentagem de células dendríticas ativadas (DCs) (CD11b+MHCII+) e o aumento no percentual de DCs tolerogênicas (CD11b-CD103+) sugere o estabelecimento deum perfil regulador neste local. Nos linfonodos inguinais foi detectado um aumento discreto na expressão dos fatores de transcrição Foxp3, Tbet e GATA-3. Estes efeitos protetores foram concomitantes com níveis elevados de selênio no SNC. Ensaios de função renal e hepática sugerem que esta eficácia terapêutica não é acompanhada de efeitos colaterais. Para reforçar a possibilidade de translação dos resultados descritos no modelo para a doença humana, testamos a eficácia terapêutica da CS em camundongos SJL/J, os quais desenvolvem uma doença do tipo remitente-recorrente. O efeito foi similar ao descrito no modelo C57BL/6. Os resultados observados reforçam nossa hipótese de que este produto tem potencial para ser utilizado como terapia adjunta em pacientes com EM.
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Its immunopathogenesis is complex and involves the interplay of distinct autoreactive T lymphocyte subsets and innate immune cells. The persistent inflammation observed in MS patients is related to oxidative stress and inflammasome activation which have been recently implicated in both, demyelination and axonal damage processes. Since the development of new therapeutic procedures remains necessary, we evaluated the efficacy of an antioxidant product to control experimental autoimmune encephalomyelitis (EAE) development. The selenized cysteine (SC) is an organic selenium, developed by a Brazilian company (Biorigin). For prophylactictherapeutic strategy, oral treatment with SC (45µg of selenium/dose) started 14 days before EAE induction and was daily extended until the acute phase of the disease. The precocious and delayed therapies have begun 1 or 7 days after MOG administration. The three therapeutic approaches reduced EAE incidence and clinical manifestations. Prophylactic-therapeutic strategy attenuated NLRP3 inflammasome activation and reduced the number of macrophages and activated microglia in the CNS. Precocious and delayed therapies were efficient in controlling EAE symptoms, reducing the percentage of macrophages and activated microglia and the MHCII expression. This protection was concomitant by less NLRP3 inflammasome activation and lower expression of mRNA for iNOS and CX3CR1. Reduction in the percentage of activated dendritic cells (DCs) (CD11b+MHCII+ ) and increase in the percentage of tolerogenic DCs (CD11b-CD103+ ) in the mesenteric lymph nodes suggest the presence of regulatory condition. Oral SC administration also slightly increase the expression of transcriptional factors Foxp3, Tbet and GATA-3 in inguinal lymph nodes. As elevated levels of selenium were determined in the CNS, we believe that SC could act directly in the neuroinflammation control. Hepatic and renal enzymes evaluation suggest that this product is safe for use. To reinforce the possibility to translate this treatment to MS patients, we evaluated SC therapeutic efficacy in a relapsing-remitting EAE model. Indeed, SC efficiently controlled the clinical manifestations in SJL/J mice. Our results emphasize that this organic selenium source has the potential to be used as an adjuvant therapy for MS patients.
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Its immunopathogenesis is complex and involves the interplay of distinct autoreactive T lymphocyte subsets and innate immune cells. The persistent inflammation observed in MS patients is related to oxidative stress and inflammasome activation which have been recently implicated in both, demyelination and axonal damage processes. Since the development of new therapeutic procedures remains necessary, we evaluated the efficacy of an antioxidant product to control experimental autoimmune encephalomyelitis (EAE) development. The selenized cysteine (SC) is an organic selenium, developed by a Brazilian company (Biorigin). For prophylactictherapeutic strategy, oral treatment with SC (45µg of selenium/dose) started 14 days before EAE induction and was daily extended until the acute phase of the disease. The precocious and delayed therapies have begun 1 or 7 days after MOG administration. The three therapeutic approaches reduced EAE incidence and clinical manifestations. Prophylactic-therapeutic strategy attenuated NLRP3 inflammasome activation and reduced the number of macrophages and activated microglia in the CNS. Precocious and delayed therapies were efficient in controlling EAE symptoms, reducing the percentage of macrophages and activated microglia and the MHCII expression. This protection was concomitant by less NLRP3 inflammasome activation and lower expression of mRNA for iNOS and CX3CR1. Reduction in the percentage of activated dendritic cells (DCs) (CD11b+MHCII+ ) and increase in the percentage of tolerogenic DCs (CD11b-CD103+ ) in the mesenteric lymph nodes suggest the presence of regulatory condition. Oral SC administration also slightly increase the expression of transcriptional factors Foxp3, Tbet and GATA-3 in inguinal lymph nodes. As elevated levels of selenium were determined in the CNS, we believe that SC could act directly in the neuroinflammation control. Hepatic and renal enzymes evaluation suggest that this product is safe for use. To reinforce the possibility to translate this treatment to MS patients, we evaluated SC therapeutic efficacy in a relapsing-remitting EAE model. Indeed, SC efficiently controlled the clinical manifestations in SJL/J mice. Our results emphasize that this organic selenium source has the potential to be used as an adjuvant therapy for MS patients.
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Palavras-chave
encefalomielite autoimune experimental, selênio, cisteína selenizada, inflamassoma, microglia, experimental autoimmune encephalomyelitis, selenium, selenized cysteine, inflammasome