Tapias Victor, González-Andrés Paula, Peña Laura F, Barbero Asunción, Núñez Lucía, Villalobos Carlos
Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, Spain.
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, 47003 Valladolid, Spain.
Antioxidants (Basel). 2023 Jun 15;12(6):1282. doi: 10.3390/antiox12061282.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca dyshomeostasis, plays a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca homeostasis and signaling has been reported, including decreased Ca uptake through voltage-operated Ca channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca homeostasis and trafficking, as well as their ability to regulate compromised mitochondrial function and associated free-radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.
阿尔茨海默病（AD）和帕金森病（PD）是老年人中最常见的两种神经退行性疾病。这些疾病的关键组织病理学特征是存在异常蛋白质聚集体以及特定脑区神经元的进行性和不可逆丧失。AD或PD发病机制的确切原因尚不清楚，但有大量证据表明，活性氧（ROS）和活性氮（RNS）的过度产生，以及抗氧化系统耗竭、线粒体功能障碍和细胞内钙稳态失调，在这些神经疾病的病理生理学中起着至关重要的作用。由于预期寿命的提高，与年龄相关的神经退行性疾病的发病率显著增加。然而，目前尚无有效的保护性治疗方法，只有非常有限的姑息治疗。因此，迫切需要开发预防策略和疾病修饰疗法来治疗AD/PD。由于钙代谢失调会导致这些疾病中的氧化损伤和神经病理学改变，鉴定或开发能够恢复钙稳态和信号传导的化合物可能为治疗神经退行性疾病提供一条神经保护途径。此外，已经报道了一系列控制线粒体钙稳态和信号传导的策略，包括通过电压门控钙通道（VOCCs）减少钙摄取。在本文中，我们综述了几种杂环化合物对钙稳态和转运的调节作用，以及它们在AD或PD发生和发展过程中调节受损线粒体功能和相关自由基产生的能力。这篇综述还描述了杂环化合物的化学合成，并总结了临床试验结果。
