Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Pharmacol Res. 2020 Feb;152:104593. doi: 10.1016/j.phrs.2019.104593. Epub 2019 Dec 13.
Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and Lewy pathology. PD is a major concern of today's aging population and has emerged as a global health burden. Despite the rapid advances in PD research over the past decades, the gold standard therapy provides only symptomatic relief and fails to halt disease progression. Therefore, exploring novel disease-modifying therapeutic strategies is highly demanded. Metformin, which is currently used as a first-line therapy for type 2 diabetes mellitus (T2DM), has recently demonstrated to exert a neuroprotective role in several neurodegenerative disorders including PD, both in vitro and in vivo. In this review, we explore the neuroprotective potential of metformin based on emerging evidence from pre-clinical and clinical studies. Regarding the underlying molecular mechanisms, metformin has been shown to inhibit α-synuclein (SNCA) phosphorylation and aggregation, prevent mitochondrial dysfunction, attenuate oxidative stress, modulate autophagy mainly via AMP-activated protein kinase (AMPK) activation, as well as prevent neurodegeneration and neuroinflammation. Overall, the neuroprotective effects of metformin in PD pathogenesis present a novel promising therapeutic strategy that might overcome the limitations of current PD treatment.
帕金森病（PD）是一种破坏性的神经退行性疾病，其特征是黑质致密部（SNpc）中的多巴胺能神经元进行性丧失和路易体病理。PD 是当今老龄化人口的主要关注点，已成为全球健康负担。尽管在过去几十年中 PD 研究取得了快速进展，但金标准疗法仅提供症状缓解，无法阻止疾病进展。因此，探索新的疾病修饰治疗策略是非常需要的。二甲双胍目前被用作 2 型糖尿病（T2DM）的一线治疗药物，最近在包括 PD 在内的几种神经退行性疾病中，无论是在体外还是在体内，都显示出具有神经保护作用。在这篇综述中，我们根据临床前和临床研究的新证据，探讨了二甲双胍的神经保护潜力。关于潜在的分子机制，二甲双胍已被证明可以抑制α-突触核蛋白（SNCA）的磷酸化和聚集，防止线粒体功能障碍，减轻氧化应激，通过 AMP 激活的蛋白激酶（AMPK）激活来调节自噬，以及预防神经退行性变和神经炎症。总的来说，二甲双胍在 PD 发病机制中的神经保护作用提出了一种新的有前途的治疗策略，可能克服当前 PD 治疗的局限性。
