Highly Selective Cyclooxygenase-1 Inhibitors P6 and Mofezolac Counteract Inflammatory State both In Vitro and In Vivo Models of Neuroinflammation.
Highly Selective Cyclooxygenase-1 Inhibitors P6 and Mofezolac Counteract Inflammatory State both In Vitro and In Vivo Models of Neuroinflammation.
复制标题
DOI：
10.3389/fneur.2017.00251
复制
发表时间：
2017
影响因子：
3.4
通讯作者：
Scilimati A
中科院分区：
文献类型：
--
作者：
Calvello R;Lofrumento DD;Perrone MG;Cianciulli A;Salvatore R;Vitale P;De Nuccio F;Giannotti L;Nicolardi G;Panaro MA;Scilimati A
活化的小胶质细胞分泌一系列促炎因子，如胡萝卜素，其积累有助于神经元损伤。前列腺素内过氧化物酶或环氧合酶（考克斯-1和考克斯-2）在炎症中起关键作用，是用于治疗疼痛和炎症的非甾体抗炎药的药理学靶点。由于据报道，考克斯-1是介导脑炎症反应的主要参与者，本研究的目的是评估高选择性考克斯-1抑制剂，如P6和莫非唑酸，在神经炎症模型中的作用。脂多糖（LPS）激活的小鼠BV-2小胶质细胞和LPS脑室内注射小鼠作为体外和体内神经炎症模型，分别用于探测P6和莫非唑酸的抗炎功效。P6和莫非唑酸均降低LPS激活的BV-2细胞中考克斯-1的表达。这种减少伴随着PGE 2释放减少和NF-kB活化下调。共同广泛，在体内模型中，神经胶质细胞酸性蛋白和离子化钙结合衔接分子-1的表达，炎症的两个标志物，减少了mofezolac的排名取决于分析的脑面积。在LPS处理的小鼠的所有脑切片中观察到的考克斯-1表达的增加被莫非唑酸体内处理以及在测试的脑区域中测定的PGE 2释放和Ikβα磷酸化量选择性地下调。这些结果表明P6和莫非唑酸调节NF-κ B信号通路的能力，强调了考克斯-1抑制剂在控制神经炎性疾病中的神经保护作用和治疗潜力。
Activated microglia secrete an array of pro-inflammatory factors, such as prostaglandins, whose accumulation contributes to neuronal damages. Prostaglandin endoperoxide synthases or cyclooxygenases (COX-1 and COX-2), which play a critical role in the inflammation, are the pharmacological targets of non-steroidal anti-inflammatory drugs, used to treat pain and inflammation. Since it was reported that COX-1 is the major player in mediating the brain inflammatory response, the aim of this study was to evaluate the effects of highly selective COX-1 inhibitors, such as P6 and mofezolac, in neuroinflammation models. Lipopolysaccharide (LPS)-activated mouse BV-2 microglial cells and LPS intracerebroventricular-injected mice as in vitro and in vivo neuroinflammation models, respectively, were used to probe the antiinflammatory efficacy of P6 and mofezolac. Both P6 and mofezolac reduce COX-1 expression in LPS-activated BV-2 cells. This reduction was accompanied with PGE2 release reduction and NF-kB activation downregulation. Coextensively, in the in vivo model, both glial fibrillary acidic protein and ionized calcium-binding adapter molecule-1 expression, two markers of inflammation, were reduced by mofezolac to a rank depending on the encephalon area analyzed. The increase of COX-1 expression observed in all the brain sections of LPS-treated mice was selectively downregulated by the in vivo treatment with mofezolac as well as PGE2 release and Ikβα phosphorylation amount assayed in the brain areas tested. These results indicate the capability of P6 and mofezolac to modulate the NF-kB signaling pathway, emphasizing the neuroprotective effect and therapeutic potential of COX-1 inhibitors in the control of neuroinflammatory diseases.