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

作　　者：Andrew RClark Chia George Hsu M A Hassan Talukder Mark Noble John CElfar 

机构地区：[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

出　　处：《Neural Regeneration Research》2020年第1期136-144,共9页中国神经再生研究（英文版）

基　　金：supported by grants from the National Institutes of Health(K08 AR060164-01A);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：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.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-4 AP 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.

关 键 词：4-AMINOPYRIDINE electron microscopy functional recovery NERVE conduction velocity PERIPHERAL NERVE injury PHARMACOKINETICS TRANSDERMAL administration 

分 类 号：R452[医药卫生—治疗学] R363[医药卫生—临床医学]