Department of Biology, University of Padova, Padova, Italy.
Parkinson and Movement Disorders Unit, Department of Neuroscience, University of Padova, Padova, Italy.
Curr Neuropharmacol. 2021;19(10):1618-1639. doi: 10.2174/1570159X19666210203162617.
Parkinson's disease (PD) is a clinically heterogeneous disorder with a multi-factorial pathology. Various molecular mechanisms are involved in the pathogenesis of PD, converging to oxidative stress and proteinopathy. The accumulation of reactive aldehydes (i.e., the dopamine metabolite DOPAL, lipid-peroxidation products, and advanced glycation end-products) has been reported in PD patients' brains. Aldehydes easily react with primary amines such as lysine residues, which are involved in several regulatory processes in cells. Therefore, aldehyde adducts lead to severe consequences, including neuronal proteostasis, mitochondrial dysfunction, and cell death. In this review, we analyzed the scavenging role of amines toward toxic aldehydes in the brain. Interestingly, small molecules like metformin, rasagiline, hydralazine are already clinically available and used in the therapy for PD and other diseases. Hence, we propose to reevaluate this class of drugs as a disease-modifiers for PD, and we suggest that improved analysis of their pharmacology and bioavailability in the brain, together with a more precise patients stratification, should be considered before planning future clinical trials.
帕金森病（PD）是一种临床表现高度异质性的疾病，具有多种发病因素。各种分子机制参与了 PD 的发病过程，其最终都汇聚到氧化应激和蛋白病这一共同通路。有研究报道称，帕金森病患者的大脑中存在大量的活性醛（如多巴胺代谢产物 DOPAL、脂质过氧化产物和晚期糖基化终产物）。醛类物质很容易与赖氨酸等一级胺发生反应，而赖氨酸在细胞的几个调节过程中都有参与。因此，醛类加合物会导致严重的后果，包括神经元蛋白稳态、线粒体功能障碍和细胞死亡。在这篇综述中，我们分析了脑中胺类物质对有毒醛的清除作用。有趣的是，二甲双胍、雷沙吉兰、肼屈嗪等小分子药物已经在临床上用于治疗 PD 和其他疾病。因此，我们建议重新评估这类药物作为 PD 的疾病修饰治疗药物，我们建议在计划未来的临床试验之前，应考虑改进它们在大脑中的药理学和生物利用度分析，并对患者进行更精确的分层。
