NSAID and antioxidant prevention of Alzheimer's disease lessons from in vitro and animal models
NSAID and antioxidant prevention of Alzheimer's disease lessons from in vitro and animal models
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DOI：
10.1196/annals.1332.005
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Frautschy, SA
中科院分区：
文献类型：
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作者：
Cole, GM;Morihara, T;Frautschy, SA
阿尔茨海默病（AD）患者脑中氧化损伤和炎症均升高，但其致病意义尚不清楚。AD风险降低与非甾体抗炎药（NSAID）和抗氧化剂的高摄入量相关;表明因果关系，但AD患者的临床试验仅产生有限或阴性结果。为了测试候选方法的潜在功效和机制，我们已经在AD的细胞培养物和动物模型（包括衰老APPsw转基因小鼠和可溶性A β啮齿动物输注模型）中探索了常规和非常规MAIDS、抗氧化剂和组合NSAID/抗氧化剂。常规NSAID布洛芬具有最强的流行病学支持。在可持续剂量设计，以模仿流行病学中的保护性消费，布洛芬减少淀粉样蛋白的积累，但抑制了令人惊讶的有限子集的炎性标志物在APPsw转基因小鼠。A β产生（APP，β-和γ-分泌酶）和产生后途径（影响A β聚集或清除的途径：例如，IL-1或α 1 ACT）可能参与布洛芬和其他NSAID抗AD活性。可以预见的是，生产后途径与其他看似保护性的NSAID共享，包括在体外不降低A β 42的萘普生。使用临床上可行的剂量，NSAID的脑水平似乎太低，无法暗示已经在体外证明的许多药理学剂量目标。Iceland不抑制与吞噬作用相关的小胶质细胞标志物。假定的抗炎ω-3脂肪酸DHA对发病机制有深远的影响，但并没有降低炎症，而维生素E在减少老年APPsw小鼠的氧化损伤或淀粉样蛋白方面令人惊讶地无效。相比之下，非传统的NSAID/抗氧化剂姜黄素是有效的，降低氧化损伤，认知缺陷，突触标记物丢失和淀粉样蛋白沉积。姜黄素被证明是免疫调节，同时抑制细胞因子和小胶质细胞活化指数相关的神经毒性，但增加吞噬指数。姜黄素直接靶向A β，并且在其他模型中也有效，从而促进了进一步的临床前和临床探索。
Both oxidative damage and inflammation are elevated in brains of Alzheimer's disease (AD) patients, but their pathogenic significance remains unclear. The reduced AD risk associated with high intake of both nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants; suggests causal roles, but clinical trials in AD patients have yielded only limited or negative results. To test the potential efficacy and mechanisms of candidate approaches, we have explored conventional and unconventional MAIDS, antioxidants, and combined NSAID/antioxidants in cell culture and animal models for AD (including aging APPsw transgenic mice and soluble A beta rodent infusion models). The conventional NSAID ibuprofen has the strongest epidemiological support. At sustainable doses designed to mimic protective consumption in the epidemiology, ibuprofen reduces amyloid accumulation but suppresses a surprisingly limited subset of inflammatory markers in APPsw transgenic mice. Both A beta production (APP, beta- and gamma-secretases) and post-production pathways (those affecting A beta aggregation or clearance: e.g., IL-1 or alpha 1ACT) are potentially involved in ibuprofen and other NSAID anti-AD activities. The post-production pathways are predictably shared with other seemingly protective NSAIDs, including naproxen that do not lower A beta 42 in vitro. Using clinically feasible dosing, brain levels of NSAIDs appear too low to implicate a number of pharmacological dose targets that have been demonstrated in vitro. Ibuprofen did not suppress microglial markers related to phagocytosis. The putative anti-inflammatory omega-3 fatty acid DHA had a profound impact on pathogenesis but did not lower inflammation, while vitamin E was surprisingly ineffective in reducing oxidative damage or amyloid in the aged APPsw mouse. In contrast, the unconventional NSAID/antioxidant curcumin was effective, lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid deposition. Curcumin proved to be immunomodulatory, simultaneously inhibiting cytokine and microglial activation indices related to neurotoxicity, but increasing an index of phagocytosis. Curcumin directly targeted A beta and was also effective in other models, warranting further preclinical and clinical exploration.