PDF(Pubmed)
Abstract：
Therapeutics discovery and development for Alzheimer\'s disease (AD) has been an area of intense research to alleviate memory loss and the underlying pathogenic processes. Recent drug discovery approaches have utilized in silico computational strategies for drug candidate selection which has opened the door to repurposing drugs for AD. Computational analysis of gene expression signatures of patients stratified by the APOE4 risk allele of AD led to the discovery of the FDA-approved drug bumetanide as a top candidate agent that reverses APOE4 transcriptomic brain signatures and improves memory deficits in APOE4 animal models of AD. Bumetanide is a loop diuretic which inhibits the kidney Na+-K+-2Cl- cotransporter isoform, NKCC2, for the treatment of hypertension and edema in cardiovascular, liver, and renal disease. Electronic health record data revealed that patients exposed to bumetanide have lower incidences of AD by 35%-70%. In the brain, bumetanide has been proposed to antagonize the NKCC1 isoform which mediates cellular uptake of chloride ions. Blocking neuronal NKCC1 leads to a decrease in intracellular chloride and thus promotes GABAergic receptor mediated hyperpolarization, which may ameliorate disease conditions associated with GABAergic-mediated depolarization. NKCC1 is expressed in neurons and in all brain cells including glia (oligodendrocytes, microglia, and astrocytes) and the vasculature. In consideration of bumetanide as a repurposed drug for AD, this review evaluates its pharmaceutical properties with respect to its estimated brain levels across doses that can improve neurologic disease deficits of animal models to distinguish between NKCC1 and non-NKCC1 mechanisms. The available data indicate that bumetanide efficacy may occur at brain drug levels that are below those required for inhibition of the NKCC1 transporter which implicates non-NKCC1 brain mechansims for improvement of brain dysfunctions and memory deficits. Alternatively, peripheral bumetanide mechanisms may involve cells outside the central nervous system (e.g., in epithelia and the immune system). Clinical bumetanide doses for improved neurological deficits are reviewed. Regardless of mechanism, the efficacy of bumetanide to improve memory deficits in the APOE4 model of AD and its potential to reduce the incidence of AD provide support for clinical investigation of bumetanide as a repurposed AD therapeutic agent.
摘要：
阿尔茨海默病（AD）的治疗发现和发展一直是缓解记忆丧失和潜在致病过程的深入研究领域。最近的药物发现方法已利用计算机计算策略进行药物候选物选择，这为将药物重新用于AD打开了大门。通过对AD的APOE4风险等位基因进行分层的患者的基因表达特征的计算分析导致发现FDA批准的药物布美他尼作为一种顶级候选药物，可以逆转APOE4转录组脑特征并改善APOE4动物模型的记忆缺陷。布美他尼是一种环路利尿剂，抑制肾脏Na+-K+-2Cl-协同转运蛋白同工型，NKCC2，用于治疗心血管高血压和水肿，肝脏,和肾脏疾病。电子健康记录数据显示，接受布美他尼治疗的患者AD发病率降低35%-70%。在大脑中,已提出布美他尼拮抗介导细胞吸收氯离子的NKCC1同工型。阻断神经元NKCC1导致细胞内氯化物减少，从而促进GABA能受体介导的超极化，这可能会改善与GABA能介导的去极化相关的疾病状况。NKCC1在神经元和所有脑细胞中表达，包括神经胶质（少突胶质细胞，小胶质细胞,和星形胶质细胞）和脉管系统。考虑到布美他尼作为AD的再用途药物，这篇综述评估了其在不同剂量下的估计脑水平的药物特性,这些剂量可以改善动物模型的神经系统疾病缺陷,以区分NKCC1和非NKCC1机制.现有数据表明，布美他尼的功效可能发生在低于抑制NKCC1转运蛋白所需水平的脑药物水平，这暗示非NKCC1大脑机制改善脑功能障碍和记忆缺陷。或者，外周布美他尼机制可能涉及中枢神经系统外的细胞(例如，在上皮和免疫系统中）。对改善神经功能缺损的临床布美他尼剂量进行了综述。不管机制如何,在AD的APOE4模型中,布美他尼改善记忆障碍的功效及其降低AD发病率的潜力,为布美他尼作为再利用AD治疗剂的临床研究提供了支持.
