Neural Regeneration Research ›› 2020, Vol. 15 ›› Issue (11): 2098-2107.doi: 10.4103/1673-5374.280319

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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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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