中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (11): 2098-2107.doi: 10.4103/1673-5374.280319

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

人体等效剂量4-氨基吡啶灌胃给药可区分小鼠坐骨神经损伤类型并改善其功能

  

  • 出版日期:2020-11-15 发布日期:2020-08-23
  • 基金资助:

    这项工作得到了美国国立卫生研究院和国防部以及罗彻斯特大学和宾夕法尼亚大学州立大学医学资助

Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice

Chia George Hsu2, M A Hassan Talukder1, Li Yue3, Loel C. Turpin4, Mark Noble5, 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 Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    3 Department of Orthopedics, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI, USA
    4 Department of Neuroscience, The University of Rochester Medical Center, Rochester, NY, USA
    5 Department of Biomedical Genetics, The University of Rochester Medical Center, Rochester, NY, USA
  • Online:2020-11-15 Published:2020-08-23
  • Contact: John C. Elfar, MD,openelfar@gmail.com.
  • Supported by:
    This work was supported by grants from the National Institutes of Health (NIH; K08 AR060164-01A) and the Department of Defense (DoD; W81XWH-16-1-0725) to JCE in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers.

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摘要：

4-氨基吡啶是FDA批准的用于多发性硬化症治疗的药物，可改善患者的神经肌肉功能。我们最近的研究证明，4-氨基吡啶的局部、透皮或注射形式可改善小鼠创伤性周围神经损伤后的髓鞘形成、神经传导速度、肌肉萎缩和运动功能。虽然口服4-氨基吡啶是临床上最常用的药物，但尚不知道人体等效剂量的4-氨基吡啶口服剂量是否会对动物的创伤性周围神经损伤分化、髓鞘形成、肌肉萎缩、功能恢复和损伤后炎症过程产生影响。坐骨神经挤压或横断伤小鼠单独接受灌胃或腹腔注射4-氨基吡啶（10 µg）或其溶剂，并检测4-氨基吡啶药代动力学，小鼠运动功能、肌肉质量、固有肌力、神经形态和基因表达谱。线性药代动力学结果显示，最大血浆4-氨基吡啶浓度与4-氨基吡啶剂量成正比。急性单剂量口服4-氨基吡啶给药可导致运动功能快速短暂改善，这在有或没有神经连续性创伤性周围神经损伤间有所不同；慢性每日口服4-氨基吡啶治疗可显著增强挤压伤后的运动功能恢复，且这种作用与相关髓鞘形成，肌肉质量和离体肌肉力量的改善有关。挤压伤神经的PCR阵列分析显示，涉及轴突炎症和再生的基因发生了显著变化。以上结果表明，无论采用何种给药途径，4-氨基吡啶均可在有或没有神经连续性的情况下迅速区分创伤性周围神经损伤类型，并可以更好地保留髓鞘、肌肉质量和肌肉力量来促进功能恢复。

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

关键词: 4-氨基吡啶, 电子显微镜, 功能恢复, 基因表达, 肌肉力量;口服给药, 药代动力学, 坐骨神经挤压伤, 坐骨神经去神经损伤

Abstract: 4-Aminopyridine (4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic pe- ripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP (10 µg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve con- tinuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. 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 of nerves, functional recovery, gene expression, muscle force, muscle mass, oral administration, pharmacokinetics, sciatic nerve crush injury, sciatic nerve denervation injury