中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (8): 3788-3796.doi: 10.4103/NRR.NRR-D-24-00941

• 原著:退行性病与再生 • 上一篇    下一篇

利司那肽抑制帕金森病α-突触核蛋白病理学传播:发挥神经保护作用的新见解

  

  • 出版日期:2026-08-18 发布日期:2026-04-28

Neuroprotective effects of lixisenatide against propagation of α-synuclein pathology in Parkinson’s disease

Shangqi Sun1, 2, Liqin Huang2, Gege Jiang2, Guanfeng Xie2, Xiaoyi Li2, Xiufeng Wang1, Hongxiu Guo1, Cailin Wang1, Siyi Zheng1, Gang Li1, *, Jing Xiong2, 3, *   

  1. 1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; 
    2Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; 
    3Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei Province, China
  • Online:2026-08-18 Published:2026-04-28
  • Contact: Jing Xiong, PhD, xiongjing@whu.edu.cn; Gang Li, PhD, gangli2008@hust.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 82271446 (to JX).

摘要:

胰高血糖素样肽1受体激动剂最初是为治疗2型糖尿病而开发的,目前已被认为是治疗帕金森病的潜在药物。一些有关胰高血糖素样肽1受体激动剂和帕金森病的临床试验表明,胰高血糖素样肽1受体激动剂可以改善帕金森病患者的运动功能障碍和生活能力。然而,胰高血糖素样肽1受体激动剂的神经保护作用的机制仍尚待清晰阐明。实验利用α-突触核蛋白预成纤维刺激诱导构建体外和体内帕金森病模型,并观察短效胰高血糖素样肽1受体激动剂利司那肽对α-突触核蛋白传播的影响。结果显示,在α-突触核蛋白预成纤维诱导的细胞模型中,利司那肽可减少α-突触核蛋白磷酸化、聚集和传播,同时减少线粒体功能障碍和细胞凋亡。此外,将α-突触核蛋白预成纤维立体定向注射到野生型小鼠纹状体后20周,利司那肽干预缓解了α-突触核蛋白预成纤维诱导的运动功能障碍和多巴胺能细胞神经变性。利司那肽抑制了神经元淋巴细胞激活基因3介导的神经元之间α-突触核蛋白磷酸化和播种。这项研究为胰高血糖素样肽1受体激动剂治疗帕金森病的作用机制提供了新的见解。


https://orcid.org/0000-0002-2221-5972 (Jing Xiong); https://orcid.org/0000-0003-3758-5965 (Gang Li)

关键词: α-突触核蛋白传播, 疾病调节治疗, 胰高血糖素样肽1受体激动剂, 利司那肽, 淋巴细胞活化基因3, 线粒体功能障碍, 帕金森病

Abstract: Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of type 2 diabetes mellitus, have been suggested as a potential disease-modifying treatment for Parkinson’s disease. Some clinical trials of glucagon-like peptide-1 receptor agonists have demonstrated that they can alleviate motor dysfunction and improve quality of life for patients with Parkinson’s disease. However, the mechanisms underlying the neuroprotective effects of glucagon-like peptide-1 receptor agonists have yet to be elucidated. In this study, we used α-synuclein preformed fibrils to generate in vitro and in vivo models of Parkinson’s disease and investigated the effects of a short-acting glucagon-like peptide-1 receptor agonist, lixisenatide, on the propagation of α-synuclein pathology. We found that lixisenatide reduced α-synuclein phosphorylation, aggregation, and propagation in cells treated with α-synuclein preformed fibrils, and that these effects were accompanied by decreased mitochondrial dysfunction and apoptosis. Additionally, lixisenatide treatment alleviated motor dysfunction and dopaminergic cell neurodegeneration 20 weeks after stereotactic injection of α-synuclein preformed fibrils into the striatum of wild-type mice. In addition, lixisenatide inhibited α-synuclein phosphorylation and seeding between neurons, mediated by neuronal lymphocyte-activation gene 3 expression. This study provides new insights into the mechanism underlying the disease-modifying effects of glucagon-like peptide-1 receptor agonists in the treatment of Parkinson’s disease.

Key words: α-synuclein propagation, disease-modifying treatment, glucagon-like peptide-1 receptor agonists, lixisenatide, lymphocyte-activation gene 3, mitochondrial dysfunction, Parkinson’s disease