Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, 00185 Rome, Italy; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Trends Pharmacol Sci. 2021 Dec;42(12):1009-1034. doi: 10.1016/j.tips.2021.09.005. Epub 2021 Oct 4.
The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders.
氯离子转运体 NKCC1 和氯离子外排体 KCC2 是神经元氯离子浓度的关键调节因子。NKCC1/KCC2 表达比值的缺陷与多种脑部疾病有关。临床前/临床研究表明，美国食品和药物管理局批准的利尿剂布美他尼抑制 NKCC1 是多种神经疾病的临床前/临床研究中的一种潜在治疗策略。然而，布美他尼的脑穿透性差，并且通过抑制肾脏中的 NKCC2 引起不必要的利尿作用。为了克服这些问题，越来越多的研究报告了更多具有脑穿透性和/或选择性的布美他尼前药、类似物和新的分子实体。在这里，我们回顾了 NKCC1 药理学抑制作为治疗神经紊乱的有效策略的证据。我们还讨论了布美他尼再利用的优势和局限性，以及新的 NKCC1 抑制剂作为治疗脑疾病的治疗剂的益处和风险。
