中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (8): 1818-1826.doi: 10.4103/1673-5374.360242

• 原著:退行性病与再生 • 上一篇    下一篇

Exendin-4和利格列汀可减轻帕金森病模型小鼠的神经炎症反应

  

  • 出版日期:2023-08-15 发布日期:2023-02-24
  • 基金资助:
    国家自然科学基金项目（81771271，31800898，81430025，U1801681）；辽宁省重点研发计划项目（2020JH2/10300047）；广东省重点领域研究发展计划项目（2018B030337001）；盛京医院杰出科学基金项目（M0475）

Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson’s disease

Hai-Yang Yu1, Tong Sun2, Zhen Wang3, Hong Li3, Duo Xu3, Jing An1, Lu-Lu Wen1, Jia-Yi Li3, 4, Wen Li3, 4, *, Juan Feng1, *   

  1. 1Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China; 2Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China; 3Laboratory of Research in Parkinson’s Disease and Related Disorders, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; 4Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
  • Online:2023-08-15 Published:2023-02-24
  • Contact: Wen Li, MD, PhD, wli87@cmu.edu.cn; Juan Feng, MD, PhD, juanfeng@cmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81771271 (to JF), 31800898 (to WL), 81430025 (to JYL), and U1801681 (to JYL); Key Research and Development Program of Liaoning Province, No. 2020JH2/10300047 (to JF); the Key Field Research Development Program of Guangdong Province, No. 2018B030337001 (to JYL); and the Outstanding Scientific Fund of Shengjing Hospital, No. M0475 (to JF).

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摘要：

研究表明，联合使用胰高血糖素样肽1受体激动剂与二肽基肽酶4抑制剂可降低糖尿病患者帕金森病的发病率，因此，两者可能在缓解帕金森病治疗方面具有潜力。为进一步探索胰高血糖素样肽1受体激动剂与二肽基肽酶4抑制剂的作用机制，实验以1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导建立帕金森病小鼠模型，皮下注射胰高血糖素样肽1受体激动剂exendin-4和二肽基肽酶4抑制剂利拉利汀进行治疗，结果发现exendin-4和利拉利汀均可逆转帕金森病小鼠的运动功能障碍、胶质细胞活化和多巴胺能神经元死亡等疾病表现。进一步研究发现，exendin-4和利拉利汀可诱导帕金森病小鼠模型黑质中小胶质细胞向抗炎型M2型极化，并减少炎症因子的分泌。此外细胞学研究显示，exendin-4和利拉利汀处理可通过减少活性氧的产生，而抑制NLRP3/Caspase-1/白细胞介素1β通路的活化以及细胞焦亡。提示exendin-4和利拉利汀可通过调节小胶质细胞极化和NLRP3/Caspase-1/白细胞介素1β通路，减轻1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的帕金森病小鼠的神经炎症反应，从而发挥神经保护作用。因此，从抗炎角度来看，这2种药物可能成为帕金森病的新型治疗药物。

https://orcid.org/0000-0002-1815-7036 (Juan Feng)

关键词: Exendin-4, 利格列汀, 帕金森病, 神经炎症, 小胶质细胞, NLRP3炎症小体, 细胞焦亡, 1-甲基-4-苯基-1,2,3,6-四氢吡啶, 糖尿病, 老药新用

Abstract: Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson’s disease in patients with diabetes mellitus. Therefore, using these two treatments may help treat Parkinson’s disease. To further investigate the mechanisms of action of these two compounds, we established a model of Parkinson’s disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin. We found that both exendin-4 and linagliptin reversed motor dysfunction, glial activation, and dopaminergic neuronal death in this model. In addition, both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion. Moreover, in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1β pathway and subsequent pyroptosis by decreasing the production of reactive oxygen species. These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1β pathway in a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore, these two drugs may serve as novel anti-inflammatory treatments for Parkinson’s disease. 

Key words: diabetes mellitus, dipeptidyl peptidase 4 inhibitor, exendin-4, glucagon-like peptide-1 receptor agonist, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, linagliptin, microglia, neuroinflammation, NLRP3 inflammasome, Parkinson’s disease, pyroptosis