Trist Benjamin G, Hare Dominic J, Double Kay L
Brain and Mind Centre and Discipline of Pharmacology, Faculty of Medical and Health, The University of Sydney, Sydney, NSW, Australia.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Vic., Australia.
Aging Cell. 2019 Dec;18(6):e13031. doi: 10.1111/acel.13031. Epub 2019 Aug 20.
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
在全球人口老龄化的背景下，帕金森病的患病率正在迅速上升。随着患病率的增加，社会和经济成本呈指数级增长，这凸显了对有效的疾病修饰治疗的迫切需求。运动功能障碍是由黑质致密部多巴胺能神经元的丧失以及黑质纹状体通路中多巴胺的耗竭所致。虽然具体的生化机制仍不明确，但氧化应激在复杂且渐进的神经退行性级联反应中起着不可否认的作用。本综述将探讨导致衰老过程中健康黑质氧化应激高稳态的分子因素，以及这种化学环境如何使神经元在帕金森病中易受氧化损伤。将在针对该疾病细胞氧化还原活性的治疗方法迄今收效甚微的方式和原因的背景下，讨论衰老过程中氧化应激的促成因素以及作为帕金森病致病机制的情况。我们对氧化还原失衡在帕金森病病因学中的核心生化作用提出了当代观点，并认为提高我们在体内准确测量氧化应激、多巴胺能神经传递和细胞死亡途径的能力对于新疗法的开发和新型疾病生物标志物的识别都至关重要。
