Selective COX-2 inhibitor celecoxib prevents experimental autoimmune encephalomyelitis through COX-2-independent pathway
Selective COX-2 inhibitor celecoxib prevents experimental autoimmune encephalomyelitis through COX-2-independent pathway
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DOI：
10.1093/brain/awl170
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发表时间：
2006-08-01
期刊：
影响因子：
14.5
通讯作者：
Yamamura, Takashi
中科院分区：
文献类型：
--
作者：
Miyamoto, Katsuichi;Miyake, Sachiko;Yamamura, Takashi
环氧合酶（考克斯）是花生四烯酸代谢的关键酶，存在两种不同的异构体。考克斯-1在大多数组织中组成型表达，而考克斯-2在炎症部位诱导表达。考克斯-2的选择性抑制剂已被开发并已被用作抗炎剂。在这里，我们表明，新一代的考克斯-2抑制剂，塞来昔布，抑制实验性自身免疫性脑脊髓炎（EAE）。塞来昔布，而不是其他考克斯-2抑制剂，如尼美舒利，防止髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE时，在疾病诱导当天口服给药。此外，塞来昔布抑制考克斯-2缺陷小鼠的EAE，表明塞来昔布以考克斯-2非依赖性方式抑制EAE。在塞来昔布处理的小鼠中，与溶剂处理的小鼠相比，MOG特异性T细胞产生的干扰素-γ（IFN-γ）减少，MOG特异性IgG 1升高。当小鼠用塞来昔布治疗时，炎症细胞浸润到中枢神经系统和粘附分子P-选择素和细胞间粘附分子-1（ICAM-1）以及趋化因子单核细胞趋化肽-1（MCP-1）的表达受到抑制。这些结果表明，塞来昔布可能是有用的作为一个新的附加治疗剂多发性硬化症。
Cyclooxygenase (COX) is a key enzyme of arachidonic acid metabolism and exists as two distinct isoforms. COX-1 is constitutively expressed in most tissues, whereas COX-2 is inducibly expressed at the site of inflammation. Selective inhibitors of COX-2 have been developed and have been used as anti-inflammatory agents. Here, we show that a new-generation COX-2 inhibitor, celecoxib, inhibited experimental autoimmune encephalomyelitis (EAE). Celecoxib, but not other COX-2 inhibitors such as nimesulid, prevented myelin oligodendrocyte glycoprotein (MOG) induced EAE when administrated orally on the day of disease induction. Moreover, celecoxib inhibited EAE in COX-2-deficient mice, indicating that celecoxib inhibited EAE in a COX-2-independent manner. In celecoxib-treated mice, interferon-gamma (IFN-gamma) production from MOG-specific T cells was reduced and MOG-specific IgG1 was elevated compared with vehicle-treated mice. Infiltration of inflammatory cells into the central nervous system and the expression of adhesion molecules, P-selectin and intercellular adhesion molecule-1 (ICAM-1), and a chemokine, monocyte chemoattractant peptide-1 (MCP-1), were inhibited when mice were treated with celecoxib. These results suggest that celecoxib may be useful as a new additional therapeutic agent for multiple sclerosis.