Cyclooxygenase (COX)-1 Activity Precedes the COX-2 Induction in Aβ-Induced Neuroinflammation
Cyclooxygenase (COX)-1 Activity Precedes the COX-2 Induction in Aβ-Induced Neuroinflammation
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DOI：
10.1007/s12031-010-9401-6
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发表时间：
2011-09-01
影响因子：
3.1
通讯作者：
Ahmadiani, Abolhassan
中科院分区：
文献类型：
--
作者：
Dargahi, Leila;Nasiraei-Moghadam, Shiva;Ahmadiani, Abolhassan
环氧合酶的两种不同亚型COX-1和COX-2在中枢神经系统的正常生理条件下组成型表达，并且不断积累的数据表明这两种亚型可能涉及不同的病理条件。然而，COX-1 和 COX-2 的独特作用以及它们在与阿尔茨海默氏病相关的神经炎症性疾病中可能存在的相互作用是相互矛盾的问题。本研究的目的是阐明每种 COX 亚型在 β-淀粉样肽 (Aβ) 诱导的神经炎症反应中的相似作用。利用组织学和生化方法，将 Aβ 立体定位注射到大鼠前额叶皮层 13 天后，通过肿瘤坏死因子-α (TNF-α) 和 COX-2 表达增加、前列腺素 E2 (PGE2) 水平升高、星形胶质细胞增生、caspase-3 激活和神经元细胞损失证实海马神经炎症和神经元损伤。长期使用选择性 COX-1 或 COX-2 抑制剂 SC560 和 NS398 来探索 COX-1 和 COX-2 的作用。使用 COX-1 或 COX-2 选择性抑制剂或其组合进行治疗同样可以降低 TNF-α、PGE2 和 cleaved caspase-3 的水平，并减轻星形胶质细胞增生和神经元细胞损失。有趣的是，用COX-1选择性抑制剂或联合COX抑制剂治疗可阻止COX-2的诱导。这些结果表明，两种亚型的活性对于与 Aβ 相关的神经炎症状况都是有害的，但 COX-1 活性对于 COX-2 诱导是必需的，并且 COX-2 活性似乎是 PGE2 增加的主要来源。
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 beta-amyloid peptide (A beta). Using histological and biochemical methods, 13 days after stereotaxic injection of A beta into the rat prefrontal cortex, hippocampal neuroinflammation and neuronal injury were confirmed by increased expression of tumor necrosis factor-alpha (TNF-alpha) 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-alpha, 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 A beta, but COX-1 activity is necessary for COX-2 induction and COX-2 activity seems to be the main source of PGE2 increment.