中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (1): 136-144.doi: 10.4103/1673-5374.264471

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

4-氨基吡啶透皮给药促进坐骨神经挤压伤小鼠运动功能恢复和神经形态的改善

  

  • 出版日期:2020-01-15 发布日期:2020-05-20

Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice

Andrew R. Clark2, Chia George Hsu3, M A Hassan Talukder1, Mark Noble4, John C. Elfar1   

  1. 1 Center for Orthopaedic Research and Translational Science, Penn State Hershey College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA
    2 Department of Orthopaedics, The University of Rochester Medical Center, Rochester, NY, USA
    3 Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    4 Department of Biomedical Genetics, The University of Rochester Medical Center, Rochester, NY, USA
  • Online:2020-01-15 Published:2020-05-20
  • Contact: John C. Elfar, MD,openelfar@gmail.com.
  • Supported by:
    This work was supported by grants from the National Institutes of Health (K08 AR060164-01A) and Department of Defense
    (W81XWH-16-1-0725) to JCE in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers.

摘要:

临床上口服4-氨基吡啶(4-AP)用于缓解多发性硬化症状,作者最近研究证实4-氨基吡啶(4-AP)系统给药可促进创伤性外周神经损伤(TPNI)后的再髓鞘化,改善神经传导性,并促进功能恢复。由此假设,透皮4-氨基吡啶(TD-4-AP)代替口服或注射给药,也可促进创伤性外周神经损伤后的功能恢复。实验将4-氨基吡啶或其溶质二甲基亚砜应用于坐骨神经挤压伤小鼠后背下部皮肤14d。结果显示,多次透皮4-氨基吡啶干预显著改善了小鼠运动和神经传导功能,并且这些效应与退化轴突减少和髓鞘增厚有关。这些发现为4-氨基吡啶的潜在透皮应用促进创伤性外周神经损伤后的恢复提供了直接证据。动物实验于2017年3月31日经罗彻斯特大学动物研究委员会(UCAR)批准(UCAR-2009-019)。

orcid: 0000-0002-4438-7118 (John C. Elfar)

关键词:

4-氨基吡啶, 透皮给药, 药代动力学, 周围神经损伤, 功能恢复, 神经传导速度, 电子显微镜

Abstract: Oral 4-aminopyridine (4-AP) is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination, improvement of nerve conductivity, and acceleration of functional recovery. We hypothesized that, instead of oral or injection administration, transdermal 4-AP (TD-4-AP) could also improve functional recovery after traumatic peripheral nerve injury. Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability, pharmacokinetics, functional, electrophysiological, and nerve morphological properties. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose. While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function, chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls. These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration. The animal experiments were approved by the University Committee on Animal Research (UCAR) at the University of Rochester (UCAR-2009-019) on March 31, 2017.

Key words: 4-aminopyridine, electron microscopy, functional recovery, nerve conduction velocity, peripheral nerve injury, pharmacokinetics,
transdermal administration