Walker Douglas, Lue Lih-Fen
Laboratory of Neuroinflammation, Sun Health Research Institute, Sun City, Arizona, USA.
Curr Neuropharmacol. 2007 Dec;5(4):232-43. doi: 10.2174/157015907782793667.
From the initial characterizations of inflammatory responses in Alzheimer's disease (AD) affected brains, namely the demonstration of activated microglia and reactive astrocytes, complement system activation, increased production of proinflammatory cytokines, and evidence for microglial-produced neurotoxins, there was hope that reducing inflammation might be a feasible treatment for this memory-robbing disease. This hope was supported by a number of epidemiology studies demonstrating that patients who took non-steroidal anti-inflammatory drugs had significantly lower risk of developing AD. However, clinical trials of anti-inflammatories have not shown effectiveness, and in recent years, the concept of immune therapy has become a treatment option as animal studies and clinical trials with Abeta vaccines have demonstrated enhanced amyloid removal through stimulation of microglial phagocytosis.This review will examine the current status of whether inhibiting inflammation is a valid therapeutic target for treating AD; what lessons have come from the clinical trials; what new pathways and classes of agents are being considered; and how this field of research can progress towards new therapeutics. We will examine a number of agents that have shown effectiveness in reducing inflammation amongst other demonstrated mechanisms of action. The major focus of much AD drug discovery has been in identifying agents that have anti-amyloid properties; however, a number of these agents were first identified for their anti-inflammatory properties. As drug development and clinical testing is a costly and lengthy endeavor, sound justification of new therapeutic targets is required. Possible future directions for AD anti-inflammatory or immune clearance therapy will be discussed based on recent experimental data.
从最初对阿尔茨海默病（AD）受累大脑炎症反应的特征描述，即活化的小胶质细胞和反应性星形胶质细胞的证实、补体系统激活、促炎细胞因子产生增加以及小胶质细胞产生神经毒素的证据来看，人们曾希望减轻炎症可能是治疗这种剥夺记忆疾病的一种可行方法。一些流行病学研究支持了这一希望，这些研究表明服用非甾体抗炎药的患者患AD的风险显著降低。然而，抗炎药的临床试验并未显示出有效性，近年来，免疫疗法的概念已成为一种治疗选择，因为动物研究和β淀粉样蛋白疫苗的临床试验已证明通过刺激小胶质细胞吞噬作用可增强淀粉样蛋白清除。本综述将探讨抑制炎症是否是治疗AD的有效治疗靶点的现状；临床试验带来了哪些经验教训；正在考虑哪些新的途径和药物类别；以及该研究领域如何朝着新的治疗方法发展。我们将研究一些在减轻炎症以及其他已证实的作用机制方面显示出有效性的药物。许多AD药物研发的主要重点一直是识别具有抗淀粉样蛋白特性的药物；然而，其中一些药物最初是因其抗炎特性而被发现的。由于药物开发和临床试验是一项成本高昂且耗时的工作，因此需要为新的治疗靶点提供充分的理由。将根据最近的实验数据讨论AD抗炎或免疫清除疗法未来可能的方向。
