Guerrero María Dolores, Aquino Maurizio, Bruno Ines, Riccio Raffaele, Terencio María Carmen, Payá Miguel
Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Av Vicent Andrés Estellés s/n, Burjassot, Valencia, Spain.
Eur J Pharmacol. 2009 Oct 12;620(1-3):112-9. doi: 10.1016/j.ejphar.2009.08.007. Epub 2009 Aug 15.
In a previous study, we reported a new gamma-hydroxybutenolide derivative, 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH), as inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) expression in lypopolysaccharide (LPS) stimulated RAW 264.7 and TPH-1 cells, without affecting cyclooxygenase-2 (COX-2). In this study, we evaluated the in vivo effect of BTH on some acute and chronic inflammatory animal models in relation to its inhibitory profile on mPGES-1 expression. In the zymosan-induced mouse air pouch model, BTH produced a dose-dependent inhibition of prostaglandin E(2) (PGE(2)) production and mPGES-1 protein expression in pouch exudates without any effect on COX-2 protein expression. This behavior was confirmed in the chronic model of collagen-induced arthritis, where administration of BTH (5 mg/kg) clearly reduced PGE(2) and mPGES-1 expression in joint tissues, whereas COX-2 was unaffected. These effects were accompanied by the suppression of clinical and histopathological manifestations of disease such as the loss of proteoglycan, and the destruction of surface cartilage. Other enzymes participating in the metabolism of arachidonic acid, such as prostaglandin I(2) synthase, tromboxane A(2) synthase or 5-lipoxygenase were unaffected by this compound. The acetic acid-induced hyperalgesia model in LPS-sensitized mice showed a dose-dependent analgesic effect of BTH, exerting an ED(50) value of 6.2 mg/kg. Our data suggest that inhibition of mPGES-1 protein expression in acute and chronic inflammatory models by BTH, could provide a potential therapeutic target and a pharmacological tool to discern the role of the inducible enzymes COX-2 and mPGES-1 in inflammatory pathologies.
在之前的一项研究中，我们报道了一种新的γ-羟基丁烯内酯衍生物，4-苯并[b]噻吩-2-基-3-溴-5-羟基-5H-呋喃-2-酮（BTH），它可作为微粒体前列腺素E合酶-1（mPGES-1）在脂多糖（LPS）刺激的RAW 264.7和TPH-1细胞中表达的抑制剂，且不影响环氧合酶-2（COX-2）。在本研究中，我们评估了BTH对一些急性和慢性炎症动物模型的体内作用，及其对mPGES-1表达的抑制情况。在酵母聚糖诱导的小鼠气囊肿模型中，BTH对气囊肿渗出液中前列腺素E2（PGE2）的产生和mPGES-1蛋白表达产生剂量依赖性抑制，而对COX-2蛋白表达无任何影响。在胶原诱导的关节炎慢性模型中也证实了这种作用，给予BTH（5 mg/kg）可明显降低关节组织中PGE2和mPGES-1的表达，而COX-2不受影响。这些作用伴随着疾病临床和组织病理学表现的抑制，如蛋白聚糖的丢失和表面软骨的破坏。参与花生四烯酸代谢的其他酶，如前列腺素I2合酶、血栓素A2合酶或5-脂氧合酶，不受该化合物影响。在LPS致敏小鼠的醋酸诱导痛觉过敏模型中，BTH显示出剂量依赖性镇痛作用，半数有效剂量（ED50）值为6.2 mg/kg。我们的数据表明，BTH在急性和慢性炎症模型中抑制mPGES-1蛋白表达，可能为辨别诱导性酶COX-2和mPGES-1在炎症性疾病中的作用提供一个潜在的治疗靶点和药理学工具。
