Novel selective COX-1 inhibitors suppress neuroinflammatory mediators in LPS-stimulated N13 microglial cells
Novel selective COX-1 inhibitors suppress neuroinflammatory mediators in LPS-stimulated N13 microglial cells
复制标题
DOI：
10.1016/j.phrs.2011.09.009
复制
发表时间：
2012-01-01
影响因子：
9.3
通讯作者：
Scilimati, Antonio
中科院分区：
文献类型：
--
作者：
Calvello, Rosa;Panaro, Maria Antonietta;Scilimati, Antonio
COX-1在神经炎症中起着以前未被认识到的作用。基因消融或药理抑制COX-1活性可减轻炎症反应和神经元损失。在此背景下，研究了选择性COX-1抑制剂（P6、P10、SC-560、阿司匹林）和coxibs（塞来昔布和依托妥昔布）对lps刺激的小胶质细胞功能（一种世界公认的神经炎症模型）的影响，并评估了它们对COX-1/COX-2、cPGES mRNA和iNOS表达、PGE(2)和NO生成以及I kappa B α磷酸化激活NF-kappa B的影响。COX-1和COX-2的表达均被各自的选择性抑制剂完全抑制。正如预期的那样，NF-kappa B在coxibs存在时几乎完全失活，在P6存在时完全失活。P6还能显著抵消LPS，增强cPGES mRNA的表达和PGE(2)的产生。由于COX-1主要局限于小胶质细胞，它的高选择性抑制比COX-2（通过coxibs）更有可能减少神经炎症，并且已被进一步研究作为具有显著炎症成分的神经退行性疾病的潜在治疗方法和预防方法。(C) 2011 Elsevier Ltd.版权所有。
COX-1 plays a previously unrecognized part in the neuroinflammation. Genetic ablation or pharmacological inhibition of COX-1 activity attenuates the inflammatory response and neuronal loss. In this context, the effects of selective COX-1 inhibitors (P6, P10, SC-560, aspirin) and coxibs (celecoxib and etoricoxib) on LPS-stimulated microglial cell function (a worldwide accepted neuroinflammation model) were investigated, and the effects on COX-1/COX-2, cPGES mRNA and iNOS expression, PGE(2) and NO production and NF-kappa B activation by I kappa B alpha phosphorylation were evaluated. The total suppression of the expression of both COX-1 and COX-2 by their respective selective inhibitors occurred. NF-kappa B remained almost completely inactive in the presence of coxibs, as expected, and totally inactive in the presence of P6. P6 also markedly counteracted LPS enhancing cPGES mRNA expression and PGE(2) production.Since COX-1 is predominantly localized in microglia, its high selective inhibition rather than COX-2 (by coxibs) is more likely to reduce neuroinflammation and has been further investigated as a potential therapeutic approach and prevention in neurodegenerative diseases with a marked inflammatory component. (C) 2011 Elsevier Ltd. All rights reserved.