Estudo dos derivados semissintéticos em SM-2 e SM-3 obtidos de estemodina em ensaio pré-clínico de dor na atm de ratos

Abstract

Temporomandibular Disorder (TMD) refers to a set of functional disorders that manifests a wide spectrum of clinical problems. Stemodia maritima Linn is a plant that is used in several therapies in Northeast Brazil. Analogs obtained through combinatorial chemical processes of plant constituents are playing an important role in the discovery of new drugs, that can help in the treatment of TMJ pain. In this sense, this study aimed to investigate the safety, antinociceptive and anti-inflammatory efficacy of two semi-synthetic compounds, SM-2 and SM-3, derived from estemodin (SM-1), isolated from leaves of Stemodia maritima Linn, in a model of formalin-induced inflammatory hypernociception in rat TMJ. To evaluate the acute toxicity, male mice (Mus musculus; n=5) (25-30 g) received, in fasting state, SM- 2 (10 μg/kg; po), SM-3 (10 μg/kg; po ) or 0.9% saline solution, being observed in sequence for a period of 24 h, at time intervals. To assess the subchronic toxicity of mice, they were observed for 15 minutes a day, after administration of the solutions, for 14 consecutive days. On the 15th day, euthanasia was performed to evaluate biochemical parameters and histopathological analysis of the organs. For the analysis of inflammatory hyperciception, male Wistar rats (180-240g) were used, in which the groups were pre-treated orally (o.r), with saline solution (0.9%), SM-2 (1; 10μg/kg ) or SM-3 (1; 10μg/kg). After 60 minutes, an intraarticular (i.a.) injection of saline solution (50 μL, 0.9%) or formalin (50 μL, 1.5%) was applied into the TMJ, then the nociceptive behavior was evaluated for 45 min. Furthermore, the possible involvement of the hemeoxygenase-1 (HO-1) and nitric oxide (NO) pathways in the antinociceptive action mechanism of SM-2 and SM-3 was investigated. Impairment of motor activity was assessed by the rotarod test. The SM-2 SM-3 compounds during 14 days did not change weight variation, relative organ weight, biochemical and histological parameters in relation to the saline control group. SM-2 and SM-3 showed antinociceptive effects through the reduction (p< 0.05) of the behavioral nociceptive response, when compared to the formalin group, not involving the HO-1 and NO pathways in their mechanism of action. There were no motor changes in the rotarod test, they did not present toxicity and were effective in reducing formalin-induced hypernociception in the TMJ of rats, requiring further research to investigate the mechanisms of action of these semi-synthetics.