Desenvolvimento farmacêutico e efeitos de uma carboximidamida em modelo experimental de artrite gotosa

Abstract

Initial research to discover new therapeutic agents for the treatment of inflammatory and metabolic diseases led to the development of DCHA, a substance obtained through a condensation of naringenin and aminoguanidine, with antioxidant, antiglycant, antinociceptive and anti-inflammatory activities. DCHA shows promise for the treatment of inflammatory diseases. In preliminary studies, an effect was demonstrated in the paw edema model induced by zymosan (Zy), showing that, in addition to modulating acute inflammatory processes, it may present benefits in the treatment of chronic inflammatory diseases. Based on this, the objective of the present research was to study the physicochemical characteristics of DCHA, biologically evaluate its antinociceptive properties in vivo and investigate its immunomodulatory activities, both in vitro and in an experimental in vivo model of gouty arthritis. In addition, we performed an in silico analysis by molecular docking of the substance. Initially, DCHA was described regarding its physicochemical aspects. Its safety was evaluated by the HET-CAM assay, while its immunomodulatory profile was investigated in vitro. Antinociceptive properties and locomotor activity were also evaluated in vivo. In the experimental model of gouty arthritis, induction was performed by injecting monosodium urate (MSU) crystals combined with zymosan into the right hind paw of mice, a model developed in this study. The effects of DCHA were evaluated by measuring paw thickness, analyzing cytokine response, lipid peroxidation, and stereological changes in the metatarsophalangeal joint of the fourth paw digit. Molecular docking of DCHA was performed to analyze its binding layer to the NLRP3 receptor. DCHA showed low water solubility, possibly due to its degree of crystallinity (63.66%). Its nature was considered primarily lipophilic, as indicated by the partition coefficient assay. In the HET-CAM assay, the substance was considered non-irritating. In in vitro studies, it was able to reduce nitrite levels in J774 cells stimulated with LPS, in addition to decreasing the production of cytokines TNF-α and IL-1β. Without molecular docking, it exhibits high binding by the NLRP3 receptor. In in vivo models, DCHA demonstrated antinociceptive activity in the hot plate, abdominal writhing and formalin assays. In arthritic animals, intensification, measured by increased paw thickness, was efficiently caused. DCHA administration resulted in a significant reduction in paw thickness, attenuating swelling and suppressing the development of intensification. I also observed a reduction in the volume of the metatarsophalangeal cartilage of the fourth digit, resulting from the inflammatory process, but DCHA managed to preserve this volume. DCHA has peripheral and central antinociceptive effects, highlighting its potential in controlling inflammation and pain. The substance has shown promise for the treatment of gouty arthritis. However, further studies are needed, especially in the induction model and in the investigation of other stereological sessions, to deepen the knowledge about its therapeutic effects and optimize its clinical use.