The anti-inflammatory and immunomodulatory potential of braylin: Pharmacological properties and mechanisms by in silico, in vitro and in vivo approaches

作者：Espirito Santo Renan Fernandes; Meira Cassio Santana; Costa Rafael dos Santos; Souza Filho Vio Passos; Evangelista Afranio Ferreira; Goulart Trossini Gustavo Henrique; Ferreira Glaucio Monteiro; Velozo Eudes da Silva; Villarreal Cristiane Flora^*; Pereira Soares Milena Botelho

来源：PLos One, 2017, 12(6): e0179174.

DOI：10.1371/journal.pone.0179174

Braylin belongs to the group of natural coumarins, a group of compounds with a wide range of pharmacological properties. Here we characterized the pharmacological properties of braylin in vitro, in silico and in vivo in models of inflammatory/immune responses. In in vitro assays, braylin exhibited concentration-dependent suppressive activity on activated macrophages. Braylin (10-40 mu M) reduced the production of nitrite, IL-1 beta, TNF-alpha and IL-6 by J774 cells or peritoneal exudate macrophages stimulated with LPS and IFN-gamma. Molecular docking calculations suggested that braylin present an interaction pose to act as a glucocorticoid receptor ligand. Corroborating this idea, the inhibitory effect of braylin on macrophages was prevented by RU486, a glucocorticoid receptor antagonist. Furthermore, treatment with braylin strongly reduced the NF-.B-dependent transcriptional activity on RAW 264.7 cells. Using the complete Freund's adjuvant (CFA)-induced paw inflammation model in mice, the pharmacological properties of braylin were demonstrated in vivo. Braylin (12.5-100 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on CFA model. Braylin did not produce antinociception on the tail flick and hot plate tests in mice, suggesting that braylin-induced antinociception is not a centrally-mediated action. Braylin exhibited immunomodulatory properties on the CFA model, inhibiting the production of pro-inflammatory cytokines IL-1 beta, TNF-a and IL-6, while increased the anti-inflammatory cytokine TGF-beta. Our results show, for the first time, anti-inflammatory, antinociceptive and immunomodulatory effects of braylin, which possibly act through the glucocorticoid receptor activation and by inhibition of the transcriptional activity of NF-.B. Because braylin is a phosphodiesterase-4 inhibitor, this coumarin could represent an ideal prototype of glucocorticoid receptor ligand, able to induce synergic immunomodulatory effects.

• 出版日期2017-6-8