Atividades do híbrido ftalimídico doador de sulfeto de hidrogênio, 2-(2-(4-tioxo-3H-1,2-ditiol-5-il)fenoxi)etil)isoindol-1,3-tiona, em modelos de dor e inflamação.

Abstract

Phthalimide analogues are substances that exhibit activities in several experimental models and present the phthalimide ring, which is also present in the structure of thalidomide. Hydrogen sulfide (H2S) is a gaseous mediator that modulates several physiological and pathological processes, including inflammation and pain. Preclinical assays have shown that phthalimide analogues and H2S donors inhibit the release of inflammatory mediators, mechanical allodynia and inflammatory edema. The development of phthalimide or H2S-releasing hybrids constitutes an important strategy aiming to obtain molecules with increased activities. Our research group previously synthesized and evaluated the activities of a phthalimide analogue that donates nitric oxide, another gaseous mediator. Thus, in the present study, a H2S-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3- thione (PTD-H2S), was synthesized and their activities and putative mechanisms were evaluated in models of inflammation and nociceptive, neuropathic and inflammatory pain. Per os administration of PTD-H2S (125 or 250 mg/kg) reduced carrageenan- or lipopolysaccharide (LPS)-induced mechanical allodynia, and carrageenan-induced paw edema. Intraperitoneal administration of PTD-H2S (25 mg/kg) reduced mechanical allodynia and tumor necrosis factor-α, interleukin (IL)-1β and IL-6 production induced by carrageenan or LPS, as well as carrageenan-induced paw edema. The inhibitory effects induced by PTD-H2S on mechanical allodynia and IL-1β and IL-6 production induced by carrageenan or LPS were reversed by prior administration of hydroxocobalamin (300 mg/kg). Previous administration of glibenclamide (40 mg/kg), a KATP channel blocker, also reversed PTD-H2S activity in the model of mechanical allodynia induced by LPS. It was also observed that PTD-H2S (25 mg/kg) showed greater activity than its precursors, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione and β-hydroxyethylphthalimide (at equimolar doses), and NaHS (8 mg/kg), in the model of mechanical allodynia induced by LPS. In conclusion, the results of the present study demonstrate the activity of PTD-H2S in models of inflammation and inflammatory pain. Putative mechanisms mediating the effects of PTD-H2S include the release of H2S, reduction of cytokine production and the activation of KATP channels. The demonstration of these activities in models of pain and inflammation indicates that H2Sreleasing phthalimide hybrids represent candidates to drugs useful in the management of inflammatory conditions.