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https://www.arca.fiocruz.br/handle/icict/34635
NATURAL CHROMONES AS POTENTIAL ANTI-INFLAMMATORY AGENTS: PHARMACOLOGICAL PROPERTIES AND RELATED MECHANISMS
Anti-inflamatória
Cromonas
NF-κB
Citocinas
Receptores glicocorticóides
Author
Affilliation
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Eberhard Karls Universität Tübingen. Institute of Pharmaceutical Sciences. Department of Pharmaceutical Chemistry. Tübingen, Germany.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Eberhard Karls Universität Tübingen. Institute of Pharmaceutical Sciences. Department of Pharmaceutical Chemistry. Tübingen, Germany.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Eberhard Karls Universität Tübingen. Institute of Pharmaceutical Sciences. Department of Pharmaceutical Chemistry. Tübingen, Germany.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil.
Eberhard Karls Universität Tübingen. Institute of Pharmaceutical Sciences. Department of Pharmaceutical Chemistry. Tübingen, Germany.
Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Abstract
Chromones are a group of natural substances with a diversity of biological activities. Herein we assessed the pharmacological potential of three chromones (1, 2 and 3) isolated from Dictyoloma vandellianum as anti-inflammatory agents using in vitro and in vivo approaches. During in vitro screening, the production of NO and cytokines by macrophages stimulated with LPS and IFN-γ was inhibited by all chromones at concentrations (5-20 μM) that did not induce cytotoxicity. Analysis of pharmacokinetic parameters (in vitro half-life and intrinsic clearance) using human liver microsomes revealed that 3 has a superior pharmacokinetic profile, compared to 1 and 2. Treatment with 3 (100 mg/kg, ip) did not affect the mice motor performance, while 1 and 2 induced motor deficit. Taking into account the pharmacokinetic profile and absence of motor impairment, 3 was selected for further pharmacological characterization. Corroborating the data from in vitro screening, treatment of cell cultures with 3 (5-20 μM) reduced TNF-α, IL-6 and IL-1β production by stimulated macrophages. In the complete Freund's adjuvant-induced paw inflammation model in mice, 3 (25 and 50 mg/kg, ip) inhibited mechanical hyperalgesia, edema and cytokine production/release (IL-1β, IL-6 and TNF-α). 3 (5-20 μM) also reduced the transcriptional activity of NF-κB in stimulated macrophages. Furthermore, treatment with RU486, a glucocorticoid receptor (GR) antagonist, partially prevented the inhibitory effect of 3 on macrophages, indicating that this chromone exerts its anti-inflammatory effects in part through the activation of GR. The results presented herein demonstrate the pharmacological potential of natural chromones, highlighting 3 as a possible candidate for the drug discovery process targeting new anti-inflammatory drugs.
Keywords in Portuguese
AntinocicepçãoAnti-inflamatória
Cromonas
NF-κB
Citocinas
Receptores glicocorticóides
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