Comparação farmacológica dos lípides resolutivos (resolvina E1, REsolvina D1 e protectina DX) nos modelos experimentais de edema e nocicepção na pata de ratos

• Ano de defesa: 2016
• Autor(a) principal: Flávia Cristina de Sousa Fonseca
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICB - INSTITUTO DE CIÊNCIAS BIOLOGICAS; Programa de Pós-Graduação em Ciências Biológicas - Fisiologia e Farmacologia; UFMG
• Palavras-chave em Português: Ediadores lipídicos pró-resolutivos especializados (SPMs); Resolvina E1; Resolvina D1; Protectina DX; Edema; Nocicepção mecânica; Farmacologia
• Link de acesso: http://hdl.handle.net/1843/58143

Resolution of inflammation is considered currently as an active process in which endogenous mediators called specialized pro-resolving lipid mediators (SPMs) exhibit anti-inflammatory and pro-resolutive activities. The aim of the present work was to study the effect of three SPMs, namely resolvin E1 (RvE1), resolvin D1 (RvD1) and protectin DX (PDX) in experimental models of edema and mechanical hyperalgesia of the hindpaw of rats in response to different phlogogenic stimuli. The phlogogenic stimuli were: carrageenan (CG; 100 and 500 μg), histamine (H; 109 nmol), serotonin (5-HT; 5 nmol), substance P (SP; 0.7 nmol) and prostaglandin E2 (PGE2; 6 nmol), all given by intraplantar route, likewise the SPMs. The paw edema and nociception measures were taken from 0h to 24h, using a plethysmometer and an analgesimeter, respectively. Animal procedures were approved by UFMG Ethics´s Committee for Animal Use, with protocols nº 199/2014 and 376/2014. Pre-treatment (10 min before the phlogogenic stimulus) with 285 pmol RvE1 reduced the edema induced by 100 μg of CG, with no change in the edema induced by SP and PGE2, but increased the edema induced by H and 5-HT. Moreover, RvE1 decreased nociception induced by all phlogogenic stimuli used. Post-treatment (2h50 min after the phlogogenic stimulus) with the same dose of RvE1 only reduced nociception induced by 500 μg of CG. Regarding to RvD1, pre-treatment with 570 pmol reduced the edema induced by 100 μg of CG and 5-HT, with no change in the edema induced by H and PGE2, but increased the edema induced by SP. Furthermore, RvD1 decreased nociception induced by 100 μg of CG, H and 5-HT but did not change the nociception induced by SP and PGE2. Post-treatment with the same dose of RvD1 only reduced nociception induced by 500 μg of CG. Treatment with PDX showed no effect in the experimental models studied. In addition, we comparatively evaluated the effects of RvE1 and RvD1 with conventional different classes of anti-inflammatory drugs, given systemically (subcutaneous route) 30 min before GC, in special: indomethacin (INDO; 4 mg/kg), celecoxib (CX; 30 mg/kg) and dexamethasone (DEXA; 1 mg/kg). It was observed that INDO reduced edema and nociception induced by 500 µg of CG and that CX only reduced the nociception of the same dose of CG, clearly showing a different profile of activity shown by resolvins. DEXA reduced edema as well nociception induced by 100 and 500 µg of CG, showinghigher reduction percentage compared with resolvins. Thus, it is suggested that the anti-inflammatory and antinociceptive action of resolvins differ from that of nonsteroidal and steroidal anti-inflammatory drugs. In the investigation of the involvement of specific receptors in the anti-inflammatory and antinociceptive actions presented by RvE1, the compound U-75302, a leukotriene B4 receptor 1 (BLT1 receptor) specific antagonist, reversed the reduction in edema and nociception induced by CG under treatment with RvE1. Furthermore, the drugs GW 1100 and AH 7614, antagonists of the receptors GPR40 and GPR120, respectively, did not produce effect in these models. Thus, it can be suggested that the BLT1 receptor is involved in the anti-inflammatory and antinociceptive effects observed with RvE1 treatment and that GPR40 and GPR120 receptors are not involved in the actions of RvE1 in the experimental models studied. Finally, commercial samples of RvE1, RvD1 and PDX used in the present study were submitted to chromatographic analysis (HPLC-DAD) and it was verified that they had structural patterns consistent with the data described in the literature for such molecules, thus giving sound ground for our results. Thus, it can be concluded that resolvins E1 and D1, given peripherally, have the potential to be better candidates for analgesics than antiinflammatory drugs. However, their prolonged use might be associated with the development of adverse effects related to pro-inflammatory activity here detected.