Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
J Neurosci Res. 2010 Dec;88(16):3588-97. doi: 10.1002/jnr.22503. Epub 2010 Oct 1.
Cocktail treatment is an effective multidrug medication therapy for some diseases, such as cancer and AIDS, because of the additive or synergistic effect of each medicine and relief from adverse effects. Amyloid-β peptide (Aβ), which is now recognized as central to the development of Alzheimer's disease (AD), is derived from the sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases. Secretase inhibitors are one of most attractive targets for therapeutic intervention in AD. However, because β- and γ-secretases cleave not only APP but also other substrate proteins, strong inhibition of these secretases leads to severe adverse effects. Some nonsteroidal antiinflammatory drugs (NSAIDs) and cholesterol-lowering drugs (statins) can modify the production of Aβ. Here, we report that a cocktail treatment with four drugs (NSAID, statin, and β- and γ-secretase inhibitors) had additive effects on the reduction of Aβ levels in cultured cells without competing with each other. Moreover, the four-drug cocktail treatment caused no changes in processing of the γ-secretase substrate Notch. This is suggests that this cocktail treatment could be a new therapeutic approach for AD.
鸡尾酒疗法是一种有效的多药物治疗方法，可用于治疗某些疾病，如癌症和艾滋病，因为每种药物都具有相加或协同作用，并且可以减轻不良反应。淀粉样β肽（Aβ）现在被认为是阿尔茨海默病（AD）发展的核心，它是由β-和γ-分泌酶对淀粉样前体蛋白（APP）的顺序蛋白水解产生的。分泌酶抑制剂是 AD 治疗干预的最有吸引力的靶标之一。然而，由于β-和γ-分泌酶不仅切割 APP，还切割其他底物蛋白，因此对这些分泌酶的强烈抑制会导致严重的不良反应。一些非甾体抗炎药（NSAIDs）和降胆固醇药物（他汀类药物）可以改变 Aβ的产生。在这里，我们报告说，四种药物（NSAID、他汀类药物和β-和γ-分泌酶抑制剂）的鸡尾酒疗法在培养细胞中具有降低 Aβ水平的相加作用，而不会相互竞争。此外，四药鸡尾酒治疗不会改变 γ-分泌酶底物 Notch 的加工。这表明这种鸡尾酒疗法可能是 AD 的一种新的治疗方法。
