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

作     者：Chia George Hsu M A Hassan Talukder Li Yue Loel CTurpin Mark Noble John C.Elfar 

作者机构：Center for Orthopaedic Research and Translational SciencePenn State Hershey College of MedicineMilton S.Hershey Medical CenterHersheyPAUSA Department of MedicineAab Cardiovascular Research InstituteUniversity of Rochester School of Medicine and DentistryRochesterNYUSA Department of OrthopedicsThe Warren Alpert Medical School of Brown University/Rhode Island HospitalProvidenceRIUSA Department of NeuroscienceThe University of Rochester Medical CenterRochesterNYUSA Department of Biomedical GeneticsThe University of Rochester Medical CenterRochesterNYUSA 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2020年第15卷第11期

页      面：2098-2107页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：supported by grants from the National Institutes of Health(NIH K08 AR060164-01A) the Department of Defense(DoD W81XWH-16-1-0725)to JCE institutional support from the University of Rochester and Pennsylvania State University Medical Centers。 

主　　题：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 

摘      要：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 peripheral 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 continuity 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.