Gasparini Laura, Ongini Ennio, Wilcock Donna, Morgan David
Nicox Research Institute, Bresso, Milan, Italy.
Brain Res Brain Res Rev. 2005 Apr;48(2):400-8. doi: 10.1016/j.brainresrev.2004.12.029. Epub 2005 Jan 28.
Currently, there is an intense debate on the potential use of nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD). NSAIDs are among the most widely prescribed drugs for the treatment of pain, fever, and inflammation. Their effects are largely attributed to the inhibition of the enzymatic activity of cyclooxygenase (COX)-1 and -2. The apparent activity of this class of drugs stems from one critical pathological process underlying AD and other neurodegenerative disorders, i.e., the presence of chronic neuroinflammation. In fact, prolonged use of NSAIDs is associated with reduced risk of AD. Besides COX inhibition, additional mechanisms could contribute to the potential activity of NSAIDs in AD. For example, several studies show that only a few selected NSAIDs also affect beta-amyloid (Abeta) deposition and metabolism. Among the Abeta-effective NSAIDs, flurbiprofen raised particular interest because of its multiple actions on key AD hallmarks. Studies in cell lines and animal models have shown that flurbiprofen racemate, its R-enantiomer and its nitric oxide (NO)-releasing derivatives, HCT 1026 and NCX 2216, are effective on AD amyloid pathology. Moreover, HCT 1026 and NCX 2216 differentially influence the cellular component of neuroinflammation (i.e., microglia activation) in some experimental settings, i.e., HCT 1026 inhibits the activation of microglia, while NCX 2216 can either enhance or inhibit microglial activation, depending upon the experimental conditions. It is still unclear which effects on microglia will prove most beneficial. Ultimately, clinical studies in AD patients will provide the best information as to whether selected NSAIDs will improve this devastating disease.
目前，关于非甾体抗炎药（NSAIDs）在阿尔茨海默病（AD）中的潜在应用存在激烈争论。NSAIDs是治疗疼痛、发热和炎症最常用的药物之一。它们的作用主要归因于对环氧合酶（COX）-1和-2酶活性的抑制。这类药物的明显活性源于AD和其他神经退行性疾病潜在的一个关键病理过程，即慢性神经炎症的存在。事实上，长期使用NSAIDs与降低AD风险相关。除了COX抑制作用外，其他机制可能也有助于NSAIDs在AD中的潜在活性。例如，多项研究表明，只有少数几种特定的NSAIDs还会影响β-淀粉样蛋白（Aβ）的沉积和代谢。在对Aβ有效的NSAIDs中，氟比洛芬因其对AD关键特征的多种作用而引起了特别关注。细胞系和动物模型研究表明，氟比洛芬消旋体、其R-对映体及其释放一氧化氮（NO）的衍生物HCT 1026和NCX 2216对AD淀粉样病理有效。此外，在某些实验环境中，HCT 1026和NCX 2216对神经炎症的细胞成分（即小胶质细胞活化）有不同影响，即HCT 1026抑制小胶质细胞活化，而NCX 2216根据实验条件既可以增强也可以抑制小胶质细胞活化。目前仍不清楚哪种对小胶质细胞的影响将被证明是最有益的。最终，针对AD患者的临床研究将提供关于特定NSAIDs是否能改善这种毁灭性疾病的最佳信息。
