Efeito do disseleneto de m-trifluormetil difenila em modelos de dor inflamatória aguda e subcrônica em camundongos

Abstract

The inflammation is a multicelular and complex process that has an essential protective role in the body. However, it can become pathological when it acts with excessive intensity and prolong endurance. In addition, the available therapeutic options to counteract inflammation has some issues regarding efficacy and safety use. In this context, the development of novel molecules with improved pharmacological profile is necessary. The m-trifluoromethyl-dyphenil diselenide [(m-CF3-PhSe)2] is an organoselenium compound that has promising biological properties, including antinociceptive action in experimental models of nociception. Thus, the main purpose of this dissertation was to evaluate the (m-CF3-PhSe)2 anti-inflammatory action in models of acute and subchronic inflammation induced by complete Freund’s adjuvant (CFA) in Swiss adult mice. The Ethical Research Committee of Federal University of Santa Maria approved all experimental procedures carried out in the present study, which are register under the number 8081170317/2017. Initially, the physicochemical stability of (m-CF3- PhSe)2 in different storage conditions was evaluated. Our results demonstrated that independent of time and storage conditions tested (freezer [-20 ºC], refrigeration [4 ºC] or room temperature [25 ºC]) no alteration in compound content was detected, suggesting a high chemical stability of (m-CF3- PhSe)2. In the protocol 1, the acute inflammation was induced in mice by an intraplantar injection of CFA and 24 h later they received a single intragastric (i.g.) administration of (m-CF3-PhSe)2. A time- and dose-response curve was performed to assess the (m-CF3-PhSe)2 effect in the mechanical hypernociception, using the von Frey hair (VFH), paw edema and myeloperoxidase activity induced by CFA. The treatment with (m-CF3-PhSe)2 reduced the mechanical hypernociceptive behavior (10 and 1 mg/kg, i.g.) as well as mitigated the paw thickness and MPO activity (10 mg/kg, i.g.). Following, the protocol 2 evaluated the effectiveness of a repeated treatment schedule with (m-CF3-PhSe)2 against the inflammatory impairments induced by CFA in mice. The potential toxicity of such administration schedule was also assessed. Mice received an intraplantar injection of CFA and 14 days later they were treated with (m-CF3-PhSe)2 (1 mg/kg, i.g./once a day/10 days). The mechanical and thermal hypernociception were daily recorded using VFH test and hot-plate test (52 ºC), respectively. The results demonstrated that the repeated administration of (m-CF3-PhSe)2 reduced both mechanical and thermal hypernociception induced by CFA. In addition, the repeated treatment with (m-CF3-PhSe)2 restored the biochemical (edema and MPO activity of paw) and molecular (IL-1β, TNF-α e COX-2, assessed in cerebral contralateral cortex samples) impairments caused by CFA. Furthermore, the repeated (m-CF3-PhSe)2 administration triggered no alteration in locomotor and exploratory activity (number of crossing, distance and average speed), plasma biochemical parameters (hepatic, renal and cardiac function) as well as in the tissue oxidative status (liver and kidneys). Collectively, these data support the (m-CF3-PhSe)2 anti-inflammatory action, reinforcing the pharmacological potential of the compound.