Department of Genetics, Cytology and Bioengineering, Voronezh State University, Voronezh, Russia.
Neurochem Res. 2019 Oct;44(10):2273-2279. doi: 10.1007/s11064-018-02711-2. Epub 2019 Jan 7.
Instead of the progress in the understanding of etiology of Parkinson's disease (PD), effective methods to prevent the progression of the disease have not been developed and only symptomatic treatment is currently possible. One of possible pathways to slow the progression of the disease is protection of dopaminergic neurons by maintaining mitochondrial quality control in neuron cells. Recent studies showed that the most promising target for pharmacological effects on mitochondria is the Nrf2/ARE signaling cascade. It participates in the maintenance of mitochondrial homeostasis, which is provided by an optimal ratio in the processes of mitochondrial biogenesis and mitophagy, as well as the optimal ratio of ROS production and ROS scavenging. Nrf2 activators are capable of modulating these processes, maintaining mitochondrial homeostasis in neurons. In addition, Nrf2 can synergistically interact with other transcription factors, for example, PGC-1a in the regulation of mitochondrial biogenesis and YY1 with the increase of antioxidant defense. All this makes Nrf2 an optimal target for drugs that could support the mitochondrial quality control, which, in combination with antioxidant protection, can significantly slow down the pathogenesis of PD. Some of these compounds have undergone laboratory studies and are at the stage of clinical trials now.
除了在帕金森病 (PD) 病因学方面取得的进展外，目前还没有开发出预防疾病进展的有效方法，只能进行对症治疗。减缓疾病进展的一种可能途径是通过维持神经元细胞中线粒体质量控制来保护多巴胺能神经元。最近的研究表明，对线粒体具有最有前途的药理作用的靶点是 Nrf2/ARE 信号级联。它参与维持线粒体动态平衡，这是通过线粒体生物发生和自噬过程中的最佳比例以及 ROS 产生和 ROS 清除的最佳比例来提供的。Nrf2 激活剂能够调节这些过程，维持神经元中线粒体的动态平衡。此外，Nrf2 可以与其他转录因子协同相互作用，例如在调节线粒体生物发生方面与 PGC-1a 协同作用，与增加抗氧化防御方面与 YY1 协同作用。所有这些使 Nrf2 成为一种理想的药物靶点，这些药物可以支持线粒体质量控制，与抗氧化保护相结合，可显著减缓 PD 的发病机制。其中一些化合物已经经过实验室研究，现在处于临床试验阶段。
