Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
J Mol Neurosci. 2011 Sep;45(1):10-21. doi: 10.1007/s12031-010-9401-6. Epub 2010 Jun 12.
Two different isoforms of cyclooxygenases, COX-1 and COX-2, are constitutively expressed under normal physiological conditions of the central nervous system, and accumulating data indicate that both isoforms may be involved in different pathological conditions. However, the distinct role of COX-1 and COX-2 and the probable interaction between them in neuroinflammatory conditions associated with Alzheimer's disease are conflicting issues. The aim of this study was to elucidate the comparable role of each COX isoform in neuroinflammatory response induced by β-amyloid peptide (Aβ). Using histological and biochemical methods, 13 days after stereotaxic injection of Aβ into the rat prefrontal cortex, hippocampal neuroinflammation and neuronal injury were confirmed by increased expression of tumor necrosis factor-alpha (TNF-α) and COX-2, elevated levels of prostaglandin E2 (PGE2), astrogliosis, activation of caspase-3, and neuronal cell loss. Selective COX-1 or COX-2 inhibitors, SC560 and NS398, respectively, were chronically used to explore the role of COX-1 and COX-2. Treatment with either COX-1 or COX-2 selective inhibitor or their combination equally decreased the level of TNF-α, PGE2, and cleaved caspase-3 and attenuated astrogliosis and neuronal cell loss. Interestingly, treatment with COX-1 selective inhibitor or the combined COX inhibitors prevented the induction of COX-2. These results indicate that the activity of both isoforms is detrimental in neuroinflammatory conditions associated with Aβ, but COX-1 activity is necessary for COX-2 induction and COX-2 activity seems to be the main source of PGE2 increment.
两种不同的环氧化酶同工酶（COX-1 和 COX-2）在中枢神经系统的正常生理条件下持续表达，越来越多的证据表明这两种同工酶可能与不同的病理条件有关。然而，COX-1 和 COX-2 的特定作用以及它们在与阿尔茨海默病相关的神经炎症条件下的可能相互作用是相互矛盾的问题。本研究旨在阐明每个 COX 同工酶在β-淀粉样肽（Aβ）诱导的神经炎症反应中的可比作用。使用组织学和生化方法，在立体定向注射 Aβ 到大鼠前额叶皮质 13 天后，通过肿瘤坏死因子-α（TNF-α）和 COX-2 的表达增加、前列腺素 E2（PGE2）水平升高、星形胶质细胞激活、caspase-3 激活和神经元细胞丢失来确认海马神经炎症和神经元损伤。分别使用选择性 COX-1 或 COX-2 抑制剂 SC560 和 NS398 进行慢性治疗，以探索 COX-1 和 COX-2 的作用。用 COX-1 或 COX-2 选择性抑制剂或它们的组合治疗同样降低了 TNF-α、PGE2 和裂解的 caspase-3 的水平，并减弱了星形胶质细胞激活和神经元细胞丢失。有趣的是，用 COX-1 选择性抑制剂或联合 COX 抑制剂治疗可预防 COX-2 的诱导。这些结果表明，两种同工酶的活性在与 Aβ 相关的神经炎症条件下都是有害的，但 COX-1 活性对于 COX-2 的诱导是必要的，并且 COX-2 活性似乎是 PGE2 增加的主要来源。
