Evaluation of Anti-Inflammatory Activity of the New Cardiotonic Steroid γ-Benzylidene Digoxin 8 (BD-8) in Mice

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Ferreira, Davi Azevedo ; Araujo Medeiros, Anna Beatriz ; Soares, Mariana Mendonca ; Lima, Essia de Almeida ; Santos Lima de Oliveira, Gabriela Carolina ; da Silva Leite, Mateus Bernardo ; Machado, Matheus Vieira ; Ferreira Perez Villar, Jose Augusto ; Barbosa, Leandro Augusto ; Scavone, Cristoforo ; Moura, Marcelo Tigre ; Rodrigues-Mascarenhas, Sandra

• Document type: Journal article
• Source: CELLS; v. 13, n. 18, p. 19-pg., 2024-09-01.

Abstract

Cardiotonic steroids are known to bind to Na+/K+-ATPase and regulate several biological processes, including the immune response. The synthetic cardiotonic steroid gamma-Benzylidene Digoxin 8 (BD-8) is emerging as a promising immunomodulatory molecule, although it has remained largely unexplored. Therefore, we tested the immunomodulatory potential of BD-8 both in vitro and in vivo. Hence, primary mouse macrophages were incubated with combinations of BD-8 and the pro-inflammatory fungal protein zymosan (ZYM). Nitric oxide (NO) production was determined by Griess reagent and cytokines production was assessed by enzyme-linked immunosorbent assay. Inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), p-nuclear factor kappa B p65 (NF-kappa B p65), p-extracellular signal-regulated kinase (p-ERK), and p-p38 were evaluated by flow cytometry. Macrophages exposed to BD-8 displayed reduced phagocytic activity, NO levels, and production of the proinflammatory cytokine IL-1 beta induced by ZYM. Furthermore, BD-8 diminished the expression of iNOS and phosphorylation of NF-kappa B p65, ERK, and p38. Additionally, BD-8 exhibited anti-inflammatory capacity in vivo in a carrageenan-induced mouse paw edema model. Taken together, these findings demonstrate the anti-inflammatory activity of BD-8 and further reinforce the potential of cardiotonic steroids and their derivatives as immunomodulatory molecules. (AU)

• FAPESP's process: 21/06009-6 - Neuroplasticity -induced by challenge Na, K-ATPase, Klotho, glutamate, and neuroinflammation signaling cascades to reveal new therapeutic targets for aging and neurodegenerative diseases
• Grantee: Cristoforo Scavone
• Support Opportunities: Research Projects - Thematic Grants