Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.
Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.
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DOI：
10.1038/ncomms12504
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发表时间：
2016-08-11
影响因子：
16.6
通讯作者：
Brough D
中科院分区：
文献类型：
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作者：
Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
非甾体抗炎药（NSAID）抑制环氧合酶-1（考克斯-1）和考克斯-2酶。NLRP 3炎性体是一种多蛋白复合物，负责促炎细胞因子白细胞介素-1 β的加工，并与许多炎性疾病有关。在这里，我们表明，几种临床批准和广泛使用的非甾体抗炎药类芬那酯是有效的和选择性抑制剂的NLRP 3炎性体通过抑制体积调节的阴离子通道在巨噬细胞，独立于考克斯酶。氟芬那酸和甲芬那酸在气囊和腹膜中的炎症的NLRP 3依赖性啮齿动物模型中是有效的。我们还使用淀粉样蛋白β诱导的记忆丧失模型和阿尔茨海默病转基因小鼠模型显示了芬那酯的治疗效果。这些数据表明，芬那酯NSAID可以重新用作NLRP 3炎性体抑制剂和阿尔茨海默病治疗剂。 NSAID诱导的镇痛通常通过抑制考克斯酶来诱导。在这里，作者表明，芬那酯NSAID通过对体积调节阴离子通道功能的影响来抑制Nlrp 3炎性体，并且还将这些药物重新用于阿尔茨海默病啮齿动物模型中的治疗效果。
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics. NSAID-induced analgesia is typically induced by inhibition of COX enzymes. Here the authors show instead that fenamate NSAIDs inhibit the Nlrp3 inflammasome via an effect on volume-regulated anion channel function and also repurpose these drugs for therapeutic effect in rodent models of Alzheimer disease.