Di Meco Antonio, Lauretti Elisabetta, Vagnozzi Alana N, Praticò Domenico
Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
Neurobiol Aging. 2014 Nov;35(11):2458-2464. doi: 10.1016/j.neurobiolaging.2014.05.016. Epub 2014 May 27.
The enzyme 5-lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD), and its pharmacologic blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12 months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid, and tau pathology assessed. Although mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significantly less Aβ deposits and tau phosphorylation secondary to reduced γ-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease.
5-脂氧合酶（5LO）在阿尔茨海默病（AD）中表达上调，用齐留通对其进行药物阻断可减缓年轻AD小鼠中类AD表型的发展。然而，在AD病理学形成后其疗效尚不清楚。为此，从12月龄开始，对三转基因小鼠（3xTg）给予齐留通（一种选择性5LO抑制剂）或安慰剂，持续3个月，然后评估这种治疗对行为、淀粉样蛋白和tau病理学的影响。尽管接受安慰剂的小鼠记忆力恶化，但接受治疗的小鼠表现甚至比基线时更好。与安慰剂相比，接受治疗的小鼠分别由于γ-分泌酶和CDK-5激活减少，Aβ沉积和tau磷酸化显著减少。我们的数据为药理学抑制5LO作为一种可行的AD治疗方法的疾病修饰作用提供了新的见解。它们代表了将这类药物开发为该疾病临床适用疗法的临床前研究的成功完成。
