Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity
Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity
复制标题
DOI：
10.1016/s0197-4580(02)00021-0
复制
发表时间：
2002-09-01
影响因子：
4.2
通讯作者：
McGeer, PL
中科院分区：
文献类型：
--
作者：
Klegeris, A;McGeer, PL
神经炎症和氧化应激被认为是正常衰老以及与年龄相关的神经系统疾病中神经变性的促成因素。在衰老的大脑中，反应性小胶质细胞的数量不断增加，并且与阿尔茨海默病（AD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）等与年龄相关的退行性疾病的病变密切相关。在体外，受刺激的小胶质细胞或小胶质细胞样细胞会分泌神经毒性物质，并通过其呼吸爆发系统产生自由基。因此，抑制小胶质细胞激活的药物是神经保护的候选药物。我们开发了定量体外测定法来测量小胶质细胞或其他单核吞噬细胞的神经毒性。在人单核细胞 THP-1 系活化细胞的上清液中培养神经元样 SH-SY5Y 细胞，并跟踪它们的存活情况。直接测量激活细胞的呼吸爆发。我们测试了环氧合酶 (COX) 或 5-脂氧合酶 (5-LOX) 途径的抑制剂作为可能的神经保护剂。 COX途径产生炎性前列腺素，而5-LOX途径产生炎性白三烯。我们发现这两种途径的抑制剂以剂量依赖性方式抑制神经毒性。其中包括 COX-1 抑制剂吲哚美辛； COX-2抑制剂NS-398；混合COX-1/COX-2抑制剂布洛芬；吲哚美辛、布洛芬和氟比洛芬的一氧化氮（NO）衍生物； 5-LOX抑制剂REV 5901；和 5-LOX 激活蛋白 (FLAP) 抑制剂 MK-886。 FLAP 抑制剂还比吲哚美辛更有效地降低呼吸爆发活动。 COX 和 5-LOX 抑制剂的组合比单一抑制剂更有效。数据表明，COX 抑制剂和 5-LOX 抑制剂可能通过抑制小胶质细胞/巨噬细胞的毒性作用在体内发挥神经保护作用，并且两者的组合可能比任一类单一抑制剂具有更大的治疗潜力。 (C) 2002 Elsevier Science Inc. 保留所有权利。
Neuroinflammation and oxidative stress are believed to be contributing factors to neurodegeneration in normal aging, as well as in age-related neurological disorders. Reactive microglia are found in increased numbers in aging brain and are prominently associated with lesions in such age-related degenerative conditions as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). In vitro, stimulated microglia or microglial-like cells secrete neurotoxic materials and are generators of free radicals through their respiratory burst system. Agents that suppress microglial activation are therefore, candidates for neuroprotection. We have developed quantitative in vitro assays for measuring neurotoxicity of microglia or other mononuclear phagocytes. Neuronal like SH-SY5Y cells are cultured in supernatants from activated cells of the human monocytic THP-1 line and their survival is followed. Respiratory burst is directly measured on the activated cells. We tested inhibitors of the cyclooxygenase (COX) or the 5-lipoxygenase (5-LOX) pathways as possible neuroprotective agents. The COX pathway generates inflammatory prostaglandins, while the.5-LOX pathway generates inflammatory leukotrienes. We found that inhibitors of both these pathways suppressed neurotoxicity in a dose-dependent fashion. They included the COX-1 inhibitor indomethacin; the COX-2 inhibitor NS-398; the mixed COX-1/COX-2 inhibitor ibuprofen; the nitric oxide (NO) derivatives of indomethacin, ibuprofen and flurbiprofen; the 5-LOX inhibitor REV 5901; and the 5-LOX activating protein (FLAP) inhibitor MK-886. The FLAP inhibitor also reduced respiratory burst activity in a more potent manner than indomethacin. Combinations of COX and 5-LOX inhibitors Were more effective than single inhibitors. The data suggest that both COX inhibitors and 5-LOX inhibitors may be neuroprotective in vivo by suppressing toxic actions of microglia/macrophages, and that combinations of the two might have greater therapeutic potential than single inhibitors of either class. (C) 2002 Elsevier Science Inc. All rights reserved.