Ho Lap, Qin Weiping, Stetka Breton S, Pasinetti Giulio M
Department of Psychiatry, The Mount Sinai School of Medicine, Neuroinflammation Research Laboratories, New York, New York 10029, USA.
CNS Drugs. 2006;20(2):85-98. doi: 10.2165/00023210-200620020-00001.
Several epidemiological studies have indicated that the long-term use of NSAIDs, most of which are cyclo-oxygenase (COX) inhibitors, may reduce the risk of Alzheimer's disease. For this reason, anti-inflammatory COX-inhibiting NSAIDs have received increased attention in experimental and therapeutic trials for Alzheimer's disease. However, several recent efforts attempting to demonstrate a therapeutic effect of NSAIDs in Alzheimer's disease have largely failed. Clinicians and scientists currently believe that this lack of success may be attributable to two key problems: (i) clinical trials of NSAIDs have been conducted in patients with late-stage Alzheimer's disease, wherein advanced neurodegeneration may be refractory to anti-inflammatory drug treatment; and (ii) it is not known which of the large family of NSAIDs (i.e. COX-1, COX-2 or mixed inhibitors) is most efficacious in preventing Alzheimer's disease. The wide list of putative functions for COX in the brain, and the significant functional heterogeneity of NSAIDs, which appear to influence the beta-amyloid (Abeta) neuropathology associated with Alzheimer's disease via both COX-dependent and COX-independent pathways, complicate the interpretation of the mechanisms through which COX-inhibiting NSAIDs may beneficially influence Alzheimer's disease. As discussed in this review, for patients at high risk of developing Alzheimer's disease (e.g. those with mild cognitive impairment), preventative treatment with COX-inhibiting NSAIDs may ultimately represent a viable strategy in the management of clinical Alzheimer's disease. However, the recent evidence showing an increased risk of major cardiovascular events among patients treated with certain COX-1 and COX-2 inhibitors leaves many questions unanswered. We suggest that further investigation into the physiological role(s) of COXs in normal health and in disease conditions, and the identification of safer and better tolerated COX inhibitors, will provide renewed impetus to the application of anti-inflammatory strategies for the prevention and treatment of Alzheimer's disease.
多项流行病学研究表明，长期使用非甾体抗炎药（NSAIDs），其中大多数是环氧化酶（COX）抑制剂，可能会降低患阿尔茨海默病的风险。因此，具有抗炎作用的COX抑制性NSAIDs在阿尔茨海默病的实验和治疗试验中受到了越来越多的关注。然而，最近几项试图证明NSAIDs对阿尔茨海默病具有治疗效果的研究大多以失败告终。临床医生和科学家目前认为，这种失败可能归因于两个关键问题：（i）NSAIDs的临床试验是在晚期阿尔茨海默病患者中进行的，而晚期神经退行性变可能对抗炎药物治疗无效；（ii）尚不清楚在众多NSAIDs家族（即COX-1、COX-2或混合抑制剂）中，哪一种在预防阿尔茨海默病方面最有效。COX在大脑中的假定功能众多，且NSAIDs具有显著的功能异质性，它们似乎通过COX依赖性和COX非依赖性途径影响与阿尔茨海默病相关的β-淀粉样蛋白（Aβ）神经病理学，这使得解释COX抑制性NSAIDs可能有益地影响阿尔茨海默病的机制变得复杂。如本综述中所讨论的，对于有患阿尔茨海默病高风险的患者（例如轻度认知障碍患者），使用COX抑制性NSAIDs进行预防性治疗可能最终成为临床管理阿尔茨海默病的可行策略。然而，最近有证据表明，使用某些COX-1和COX-2抑制剂治疗的患者发生重大心血管事件的风险增加，这留下了许多未解决的问题。我们建议，进一步研究COX在正常健康和疾病状态下的生理作用，以及鉴定更安全、耐受性更好的COX抑制剂，将为应用抗炎策略预防和治疗阿尔茨海默病提供新的动力。
