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

Abstract

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 μM) reduced the production of nitrite, IL-1β, TNF-α and IL-6 by J774 cells or peritoneal exudate macrophages stimulated with LPS and IFN-γ. 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-κB-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-1β, TNF-α and IL-6, while increased the anti-inflammatory cytokine TGF-β. 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-κB. Because braylin is a phosphodiesterase-4 inhibitor, this coumarin could represent an ideal prototype of glucocorticoid receptor ligand, able to induce synergic immunomodulatory effects.

• Authors: Renan Fernandes Espírito-Santo, Cassio Santana Meira, Rafael Dos Santos Costa, Otávio Passos Souza Filho, Afranio Ferreira Evangelista, Gustavo Henrique Goulart Trossini, Glaucio Monteiro Ferreira, Eudes da Silva Velozo, Cristiane Flora Villarreal, Milena Botelho Pereira Soares
• Journal: PloS one (PLoS One) Vol. 12 Issue 6 Pg. e0179174 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28594906 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• Anti-Inflammatory Agents
• Coumarins
• Cytokines
• Immunologic Factors
• NF-kappa B
• Receptors, Glucocorticoid
• Nitric Oxide

Topics

• Adjuvants, Immunologic
• Animals
• Anti-Inflammatory Agents (chemistry, pharmacology)
• Cell Death (drug effects)
• Cell Line
• Computer Simulation
• Coumarins (chemistry, pharmacology)
• Cytokines (biosynthesis)
• Immunologic Factors (chemistry, pharmacology)
• Inflammation (pathology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Molecular Docking Simulation
• NF-kappa B (metabolism)
• Nitric Oxide (biosynthesis)
• Receptors, Glucocorticoid (metabolism)
• Transcription, Genetic (drug effects)