Bernardo Antonietta, Gasparini Laura, Ongini Ennio, Minghetti Luisa
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Neurobiol Dis. 2006 Apr;22(1):25-32. doi: 10.1016/j.nbd.2005.09.012. Epub 2005 Nov 22.
The nitric oxide-releasing derivative of flurbiprofen, NCX 2216, has a safer gastrointestinal profile than the parent drug flurbiprofen and a strong anti-amyloidogenic activity. Here, we show that in primary microglial cultures, in addition to the expected inhibition of prostaglandin synthesis, NCX 2216 specifically activated the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a ligand-dependent transcription factor controlling several important microglial functions. Prolonged treatment (16 h) of microglial cultures with NCX 2216 induced PPAR-gamma nitration and prevented further activation of the receptor by specific agonists. At functional levels, NCX 2216 treatment of LPS-activated microglial cultures resulted in the transient reduction of TNF-alpha and NO production and in the protracted inhibition of IL-1beta and PGE2 synthesis. The dynamic regulation of the functional state of activated microglia by NCX 2216 helps explaining recent findings in Alzheimer's disease animal models and may offer new therapeutic opportunities for treating neurodegenerative diseases.
氟比洛芬的一氧化氮释放衍生物NCX 2216具有比母体药物氟比洛芬更安全的胃肠道特性以及强大的抗淀粉样蛋白生成活性。在此，我们表明，在原代小胶质细胞培养中，除了预期的对前列腺素合成的抑制作用外，NCX 2216还特异性激活了过氧化物酶体增殖物激活受体γ（PPAR-γ），这是一种控制多种重要小胶质细胞功能的配体依赖性转录因子。用NCX 2216对小胶质细胞培养物进行长时间处理（16小时）会诱导PPAR-γ硝化，并阻止特异性激动剂对该受体的进一步激活。在功能水平上，用NCX 2216处理脂多糖激活的小胶质细胞培养物会导致肿瘤坏死因子-α（TNF-α）和一氧化氮（NO）产生的短暂减少，以及白细胞介素-1β（IL-1β）和前列腺素E2（PGE2）合成的长期抑制。NCX 2216对活化小胶质细胞功能状态的动态调节有助于解释阿尔茨海默病动物模型中的最新发现，并可能为治疗神经退行性疾病提供新的治疗机会。
