Scognamiglio Antonia, Corvino Angela, Caliendo Giuseppe, Fiorino Ferdinando, Perissutti Elisa, Santagada Vincenzo, Severino Beatrice
Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
Int J Mol Sci. 2025 Sep 12;26(18):8888. doi: 10.3390/ijms26188888.
Na/Ca exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation.
钠/钙交换体（NCXs）是膜转运蛋白，对可兴奋组织尤其是中枢神经系统中的钙稳态至关重要。越来越多的证据表明，NCX功能障碍在几种神经疾病中会导致钙超载和神经元损伤。因此，对NCX亚型（NCX1、NCX2和NCX3）进行药物调节已成为治疗中风、多发性硬化症（MS）、肌萎缩侧索硬化症（ALS）、阿尔茨海默病（AD）和帕金森病（PD）等疾病的一种潜在治疗策略。然而，鉴定针对特定NCX亚型甚至不同剪接变体的选择性调节剂仍然具有挑战性，并限制了它们的临床验证。本综述旨在提供过去二十年来所描述的小分子NCX调节剂的最新概述。文中讨论了化学结构、作用机制和亚型特异性，以及用于其功能评估的最常用生物学检测方法。
