中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (11): 2234-2242.doi: 10.4103/1673-5374.310695

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

脊髓损伤亚急性期较低剂量二甲双胍治疗可改善功能预后

  

  • 出版日期:2021-11-15 发布日期:2021-04-13
  • 基金资助:

    中国康复研究基金项目（MC018-112）；John S. Dunn基金会（18168）；中国国家自然科学基金项目（81620108018，81930070，82072439）；天津重点研发计划-国家科技支撑重点项目（19YFZCSY00660）；国家重点研发计划（2019YFA0112100）

Low-dose metformin treatment in the subacute phase improves the locomotor function of a mouse model of spinal cord injury

Wen-Ye Song, Han Ding, Tiffany Dunn, Jun-Ling Gao, Javier Allende Labastida, Caitlin Schlagal, Guang-Zhi Ning, Shi-Qing Feng, Ping Wu   

  1. 1Department of Neuroscience, Cell Biology & Anatomy, University of Texas Medical Branch at Galveston, Galveston, TX, USA; 2Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
  • Online:2021-11-15 Published:2021-04-13
  • Contact: Ping Wu, MD, PhD, piwu@utmb.edu; Shi-Qing Feng, MD, PhD, sqfeng@tmu.edu.cn.
  • Supported by:
    This work was supported by a grant from The Institute for Rehabilitation and Research Foundation, No. MC018-112 (to PW); John S. Dunn Foundation, No. 18168 (to PW); the National Natural Science foundation of China, Nos. 81620108018 (to SQF), 81930070 (to SQF), 82072439 (to GZN); Tianjin Key Research and Development Plan, Key Projects For Science and Technology Support of China, No. 19YFZCSY00660 (to SQF); and the National Key R&D Program of China, No. 2019YFA0112100 (to SQF).

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摘要：

二甲双胍是治疗2型糖尿病的一线药物，有研究显示其可促进脊髓损伤后运动能力的恢复，但也有研究显示没有积极的作用。作者在预实验中发现高剂量（200 mg/kg）和早期治疗可导致脊髓损伤小鼠死亡率增加和运动功能恢复受限。为此，本组实验设计在小鼠脊髓损伤后急性期（损伤后即刻）和亚急性期（损伤后3d）腹腔注射较低剂量（100 mg/kg）二甲双胍进行比较。（1）从亚急性期开始注射二甲双胍，增加了脊髓损伤小鼠BMS评分，抑制损伤脊髓中小胶质细胞/巨噬细胞和星形胶质细胞的活化，减少中性粒细胞浸润，且上述变化与脊髓神经元存活率提升情况同步；（2）结果表明，亚急性期较低剂量二甲双胍干预可有效促进脊髓损伤后运动功能的恢复，其作用可能是通过抗炎和神经保护介导的。实验于2010年经德克萨斯大学医学院动物伦理委员会批准（批准号1008041C）。

https://orcid.org/0000-0002-7020-6237 (Ping Wu)

关键词:

脊髓损伤, 二甲双胍, 运动功能, 死亡率, 炎症, 亚急性期管理, 神经保护, 小胶质细胞

Abstract: Metformin, a first-line drug for type-2 diabetes, has been shown to improve locomotor recovery after spinal cord injury. However, there are studies reporting no beneficial effect. Recently, we found that high dose of metformin (200 mg/kg, intraperitoneal) and acute phase administration (immediately after injury) led to increased mortality and limited locomotor function recovery. Consequently, we used a lower dose (100 mg/kg, i.p.) metformin in mice, and compared the effect of immediate administration after spinal cord injury (acute phase) with that of administration at 3 days post-injury (subacute phase). Our data showed that metformin treatment starting at the subacute phase significantly improved mouse locomotor function evaluated by Basso Mouse Scale (BMS) scoring. Immunohistochemical studies also revealed significant inhibitions of microglia/macrophage activation and astrogliosis at the lesion site. Furthermore, metformin treatment at the subacute phase reduced neutrophil infiltration. These changes were in parallel with the increased survival rate of spinal neurons in animals treated with metformin. These findings suggest that low-dose metformin treatment for subacute spinal cord injury can effectively improve the functional recovery possibly through anti-inflammation and neuroprotection. This study was approved by the Institute Animal Care and Use Committee at the University of Texas Medical Branch (approval No. 1008041C) in 2010.

Key words: inflammation, locomotor function, metformin, microglia, mortality, neuroprotection, spinal cord injury, subacute administration

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