Li Lanxin, Zhang Yang, Chen Zhengqian, Yao Ruyong, Xu Zhongqiu, Xu Can, He Fujie, Pei Haitao, Hao Cui
Medical Research Center, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao 266003, China.
Heliyon. 2023 Oct 26;9(11):e21695. doi: 10.1016/j.heliyon.2023.e21695. eCollection 2023 Nov.
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the substantia nigra and the formation of intraneuronal. Numerous studies showed that the damage and dysfunction of mitochondria may play key roles in DA neuronal loss. Thus, it is necessary to seek therapeutic measures for PD targeting mitochondrial function and biogenesis. In this study, through screening the purchased compound library, we found that marine derived vidarabine had significant neuroprotective effects against rotenone (ROT) induced SH-SY5Y cell injury. Further studies indicated that vidarabine pretreatment significantly protected ROT-treated SH-SY5Y cells from toxicity by preserving mitochondrial morphology, improving mitochondrial function, and reducing cell apoptosis. Vidarabine also reduced the oxidative stress and increased the expression levels of PGC-1α, NRF1, and TFAM proteins, which was accompanied by the increased mitochondrial biogenesis. However, the neuroprotective effects of vidarabine were counteracted in the presence of SIRT1-specific inhibitor Ex-527. Besides, vidarabine treatment attenuated the weight loss, alleviated the motor deficits and inhibited the neuronal injury in the MPTP induced mouse model. Thus, vidarabine may exert neuroprotective effects via a mechanism involving specific connections between the SIRT1-dependent mitochondrial biogenesis and its antioxidant capacity, suggesting that vidarabine has potential to be developed into a novel therapeutic agent for PD.
帕金森病（PD）是世界上第二常见的神经退行性疾病，其特征是黑质中多巴胺能（DA）神经元的丧失和神经元内的形成。大量研究表明，线粒体的损伤和功能障碍可能在DA神经元丧失中起关键作用。因此，有必要寻找针对线粒体功能和生物发生的帕金森病治疗措施。在本研究中，通过筛选购买的化合物库，我们发现海洋来源的阿糖腺苷对鱼藤酮（ROT）诱导的SH-SY5Y细胞损伤具有显著的神经保护作用。进一步的研究表明，阿糖腺苷预处理通过保持线粒体形态、改善线粒体功能和减少细胞凋亡，显著保护ROT处理的SH-SY5Y细胞免受毒性。阿糖腺苷还降低了氧化应激，并增加了PGC-1α、NRF1和TFAM蛋白的表达水平，同时线粒体生物发生增加。然而，在存在SIRT1特异性抑制剂Ex-527的情况下，阿糖腺苷的神经保护作用被抵消。此外，阿糖腺苷治疗减轻了MPTP诱导的小鼠模型中的体重减轻，缓解了运动缺陷，并抑制了神经元损伤。因此，阿糖腺苷可能通过一种涉及SIRT1依赖性线粒体生物发生与其抗氧化能力之间特定联系的机制发挥神经保护作用，这表明阿糖腺苷有潜力被开发成为一种新型的帕金森病治疗药物。
