Almeida Dionys de S, da Silva Daiany P B, Moreira Lorrane K da S, Menegatti Ricardo, Lião Luciano M, Sanz Germán, Vaz Boniek G, Ghedini Paulo C, Costa Elson A, Florentino Iziara F
Institute of Biological Sciences, Department of Pharmacology, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil.
Faculty of Pharmacy, Laboratory of Medicinal Pharmaceutical Chemistry, Federal University of Goiás, Goiânia, GO, Brazil.
Eur J Pharmacol. 2020 Nov 5;886:173388. doi: 10.1016/j.ejphar.2020.173388. Epub 2020 Aug 5.
The aim of this study was to synthesise the novel di-tert-butylphenol compound, 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-thioxo-dihydropyrimidine-4,6(1H, 5H)-dione (LQFM218), and evaluate the potential anti-nociceptive and anti-inflammatory activities in acute (mice) models in vivo. The compound was tested on acute models of pain such as acetic acid-induced abdominal writhing, formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The anti-inflammatory activity was observed in paw oedema, carrageenan-induced pleurisy tests and inflammatory mediator quantification. Key findings: oral treatment with the LQFM218 (50, 100 or 200 mg/kg) reduced abdominal writhing (18.8%, 31.6% and 48.3%). The dose intermediate (100 mg/kg) reduced the nociception in the second phase of the formalin test (61.4%), and also showed anti-hyperalgic activity in carrageenan-induced mechanical hyperalgesia (until 42.3%). In acute inflammation models, the treatment of mice LQFM218 (100 mg/kg) reduced the paw oedema all the time (33.8%, 42.6%, 37.4% and 36%) and in pleurisy test reduced: polymorphonuclear cell migration (35.4%), myeloperoxidase activity (52.2%) and the levels of inflammatory mediators such as PGE (23.0%), TNF-α (67.6%) and IL-1β (53.4%). The present study showed that LQFM218 effectively reduced the nociception and inflammation in different models, and its mechanism might be related to the reduction of PGE and pro-inflammatory cytokines. These findings show LQFM218 as a potential anti-inflammatory drug.
本研究的目的是合成新型二叔丁基苯酚化合物5-(3,5-二叔丁基-4-羟基亚苄基)-2-硫代二氢嘧啶-4,6(1H,5H)-二酮(LQFM218)，并在急性(小鼠)体内模型中评估其潜在的抗伤害性感受和抗炎活性。该化合物在疼痛急性模型上进行了测试，如醋酸诱导的腹部扭体、福尔马林诱导的伤害感受和角叉菜胶诱导的机械性痛觉过敏。在爪肿胀、角叉菜胶诱导的胸膜炎试验和炎症介质定量中观察到了抗炎活性。主要发现：口服LQFM218(50、100或200mg/kg)可减少腹部扭体(分别为18.8%、31.6%和48.3%)。中等剂量(100mg/kg)可降低福尔马林试验第二阶段的伤害感受(61.4%)，并对角叉菜胶诱导的机械性痛觉过敏也显示出抗痛觉过敏活性(高达42.3%)。在急性炎症模型中，用LQFM218(100mg/kg)治疗小鼠可一直减少爪肿胀(分别为33.8%、42.6%、37.4%和36%)，在胸膜炎试验中可减少：多形核细胞迁移(35.4%)、髓过氧化物酶活性(52.2%)以及炎症介质如前列腺素E(PGE)(23.0%)、肿瘤坏死因子-α(TNF-α)(67.6%)和白细胞介素-1β(IL-1β)(53.4%)的水平。本研究表明，LQFM218在不同模型中有效减轻了伤害感受和炎症，其机制可能与PGE和促炎细胞因子的减少有关。这些发现表明LQFM218是一种潜在的抗炎药物。
