Author | Guimarães, Elisalva Teixeira | |
Author | Santos, Tatiana Barbosa dos | |
Author | Silva, Dahara Keyse Carvalho | |
Author | Meira, Cássio Santana | |
Author | Moreira, Diogo Rodrigo Magalhães | |
Author | Silva, Tiago Fernandes da | |
Author | Salmon, Didier | |
Author | Barreiro, Eliezer Jesus de Lacerda | |
Author | Soares, Milena Botelho Pereira | |
Access date | 2019-01-24T13:18:40Z | |
Available date | 2019-01-24T13:18:40Z | |
Document date | 2018 | |
Citation | GUIMARÃES, Elisalva Teixeira et al. Potent immunosuppressive activity of a phosphodiesterase-4 inhibitor N-acylhydrazone in models of lipopolysaccharide-induced shock and delayed-type hypersensitivity reaction. International Immunopharmacology, v. 65, p. 108-118, 2018. | pt_BR |
ISSN | 1567-5769 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/31287 | |
Sponsorship | CNPq, FAPESB and INCTINOFAR. | pt_BR |
Language | eng | pt_BR |
Publisher | Elsevier | pt_BR |
Rights | restricted access | pt_BR |
Subject in Portuguese | Imunomodulação | pt_BR |
Subject in Portuguese | Choque endotóxico | pt_BR |
Subject in Portuguese | Reação de hipersensibilidade de tipo retardado | pt_BR |
Subject in Portuguese | Derivado de N-acil-hidrazona | pt_BR |
Title | Potent immunosuppressive activity of a phosphodiesterase-4 inhibitor N-acylhydrazone in models of lipopolysaccharide-induced shock and delayed-type hypersensitivity reaction | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.intimp.2018.09.047 | |
Abstract | Immunosuppressive drugs are widely used for the treatment of immune-mediated diseases and inflammation, but the toxicity and side effects of the available immunosuppressors make the search of new agents of great relevance. Here, we evaluated the immunomodulatory activity of an N-acylhydrazone derivative, (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), a phosphodiesterase-4 (PDE-4) inhibitor. LASSBio-1386 inhibited lymphocyte activation in a concentration-dependent fashion, decreasing lymphoproliferation and IFN-γ and IL-2 production stimulated by anti-CD3/CD28 mAbs or concanavalin A (Con A) and inducing cell-cycle arrest in the G0/G1 phase. These effects were not blocked by RU486, a glucocorticoid receptor (GR) antagonist, indicating an effect independent of glucocorticoid receptor activation. Combination index-isobologram analysis indicates a synergistic effect between LASSBio-1386 and dexamethasone in lymphoproliferation inhibition. LASSBio-1386 presented immunomodulatory action in macrophage cultures, as observed by a significant and concentration-dependent decrease in NO and TNF-α production, an effect achieved by reducing IĸB expression and NF-κB activation. In the mouse model of endotoxic shock, LASSBio-1386 at 50 and 100 mg/kg protected 50 and 85% of mice against LPS-induced lethality, respectively. In agreement to its in vitro action, treatment with 100 mg/kg of LASSBio-1386 reduced TNF-α and IL-1β serum levels, while increased IL-6 and IL-10. Finally, LASSBio-1386 reduced the paw edema in a BSA-induced delayed-type hypersensitivity model. These findings demonstrate the immunomodulatory and immunosuppressant effects of LASSBio-1386 and indicate this molecule is a promising pharmacologic agent for immune-mediated diseases. | pt_BR |
Affilliation | Universidade Estadual da Bahia. Núcleo de Estudo e Pesquisa em Histopatologia. Departamento de Ciências da Vida. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Universidade Estadual da Bahia. Núcleo de Estudo e Pesquisa em Histopatologia. Departamento de Ciências da Vida. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Universidade Estadual da Bahia. Núcleo de Estudo e Pesquisa em Histopatologia. Departamento de Ciências da Vida. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio de Janeiro. Laboratório de Avaliação e Síntese de Substâncias Bioativas. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica Leopoldo de Meis. Centro de Ciências da Saúde. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio de Janeiro. Laboratório de Avaliação e Síntese de Substâncias Bioativas. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil. | pt_BR |
Subject | Immunomodulation | pt_BR |
Subject | Endotoxic shock | pt_BR |
Subject | Delayed-type hypersensitivity reaction | pt_BR |
Subject | N-acylhydrazone derivative | pt_BR |