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 (2): 439-444.doi: 10.4103/1673-5374.346456

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

周围神经横断和缺损移植的临床前小鼠模型的功能恢复和肌肉萎缩：4-氨基吡啶的作用

  


  • 出版日期:2023-02-15 发布日期:2022-08-09

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice: effects of 4-aminopyridine

Jung Il Lee1, 2, M A Hassan Talukder1, *, Zara Karuman1, Anagha A. Gurjar1, Prem Kumar Govindappa1, Jagadeeshaprasad M. Guddadarangaiah1, Kristen M. Manto1, Grant D. Wandling1, John P. Hegarty1, David L. Waning3, John C. Elfar1, *#br#   

  1. 1Department of Orthopaedics and Rehabilitation, Center for Orthopaedic Research and Translational Science, The Pennsylvania State University College of Medicine, Hershey, PA, USA; 2Department of Orthopaedic Surgery, Korea University Guro Hospital, Seoul, South Korea; 3Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
  • Online:2023-02-15 Published:2022-08-09
  • Contact: John C. Elfar, MD, openelfar@gmail.com; M A Hassan Talukder, MD, PhD, mahassanatlaukder@yahoo.com.
  • Supported by:
    This work was supported by grants from the National Institutes of Health, USA (No. K08 AR060164-01A) and Department of Defense, USA (Nos. W81XWH-16-1-0725 and W81XWH-19-1-0773) in addition to institutional support from the Pennsylvania State University College of Medicine. 

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摘要：

作者最近研究证明了钾通道阻断剂4-氨基吡啶对啮齿动物坐骨神经压迫损伤后的功能恢复和肌肉萎缩有有益作用；然而，4-氨基吡啶在神经横断、缺损和移植模型中的这种作用尚不清楚。为了评估和比较4-氨基吡啶对周围神经横断、缺损和移植模型小鼠功能恢复、神经形态和肌肉萎缩的影响，实验在有无4-氨基吡啶治疗的情况下，采用了逐步神经横断与胶接，以及7mm神经缺损（G-7/0）和7mm同种移植物修复5mm缺损（G-5/7）模型。术后，每周测定坐骨神经功能指数，以评估运动功能恢复；12周后，对神经进行全组织包埋免疫荧光成像处理，称胫骨前肌湿重，定量组织形态学分析肌纤维横截面积和最小费雷特直径。神经横断与胶接和7mm同种移植物修复5mm缺损模型的伤后坐骨神经功能指数明显大于7mm神经缺损模型。与神经横断与胶接模型相比，接受同种神经移植小鼠的神经成像显示了更多错误的轴突和扭曲的神经结构。虽然与神经横断与胶接和7mm同种移植物修复5mm缺损模型相比，7mm神经缺损模型的肌肉重量、肌纤维横截面积和最小费雷特直径明显较小，但4-氨基吡啶治疗明显改善了7mm神经缺损模型的胫骨前肌肌肉质量、肌纤维横截面积和最小费雷特直径。这些结果表明，周围神经损伤后的功能恢复和肌肉萎缩与神经缺损程度直接相关，而4-氨基吡啶对功能恢复和肌肉萎缩产生不同的影响。

https://orcid.org/0000-0002-4438-7118 (John C. Elfar); https://orcid.org/0000-0002-8352-2247 (M A Hassan Talukder)

Abstract: We recently demonstrated a repurposing beneficial effect of 4-aminopyridine (4-AP), a potassium channel blocker, on functional recovery and muscle atrophy after sciatic nerve crush injury in rodents. However, this effect of 4-AP is unknown in nerve transection, gap, and grafting models. To evaluate and compare the functional recovery, nerve morphology, and muscle atrophy, we used a novel stepwise nerve transection with gluing (STG), as well as 7-mm irreparable nerve gap (G-7/0) and 7-mm isografting in 5-mm gap (G-5/7) models in the absence and presence of 4-AP treatment. Following surgery, sciatic functional index was determined weekly to evaluate the direct in vivo global motor functional recovery. After 12 weeks, nerves were processed for whole-mount immunofluorescence imaging, and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber cross-sectional area and minimal Feret’s diameter. Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model. 4-AP did not affect the sciatic functional index recovery in any model. Compared to STG, nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting. While muscle weight, cross-sectional area, and minimal Feret’s diameter were significantly smaller in G-7/0 model compared with STG and G-5/7, 4-AP treatment significantly increased right TA muscle mass, cross-sectional area, and minimal Feret’s diameter in G-7/0 model. These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap, and 4-AP exerts differential effects on functional recovery and muscle atrophy.

Key words: 4-aminopyridine, functional recovery, muscle atrophy, nerve gap, nerve grafting, nerve imaging, nerve transection