Research & Development Department, Chiesi Farmaceutici, Via Palermo 26/A, 43100 Parma, Italy.
Expert Opin Investig Drugs. 2009 Aug;18(8):1147-68. doi: 10.1517/13543780903066780.
Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more epsilon4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of beta-amyloid(1-42) (Abeta42) production and aggregation, inhibition of beta-secretase activity, activation of PPAR-gamma or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Abeta42. Once the Abeta deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Abeta clearance and activates compensatory hippocampal neurogenesis.
几项流行病学研究表明，长期使用非甾体抗炎药（NSAIDs）可能对阿尔茨海默病（AD）有预防作用，尤其是对携带载脂蛋白 E 一个或多个 ε4 等位基因的患者。这种保护的生物学机制尚不完全清楚，可能涉及 COX 活性抑制、β-淀粉样蛋白（1-42）（Abeta42）产生和聚集的抑制、β-分泌酶活性抑制、PPAR-γ激活或神经营养因子合成的刺激。不幸的是，AD 患者中进行的长期、安慰剂对照的非选择性和 COX-2 选择性 NSAIDs 临床试验均得出了阴性结果。在轻度认知障碍患者中进行的罗非昔布二级预防研究和在有 AD 家族史的老年患者中进行的萘普生和塞来昔布一级预防研究也均为阴性。所有这些失败都降低了 NSAIDs 对 AD 治疗有益的希望。有人假设，NSAIDs 通过抑制 Abeta42 的产生，可能仅对正常大脑有益。一旦 Abeta 沉积过程开始，NSAIDs 就不再有效，甚至可能有害，因为它们对 AD 大脑中激活的小胶质细胞的抑制作用会介导 Abeta 清除并激活代偿性海马神经发生。
