TY - JOUR
T1 - Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice
AU - Clark, Andrew
AU - Hsu, Chia
AU - Hassan Talukder, M.
AU - Noble, Mark
AU - Elfar, John
N1 - Funding Information:
Acknowledgments: We thank Loel C. Turpin (The University of Rochester Medical Center, Rochester, NY, USA) for technical support. Author contributions: Data acquisition, analysis and interpretation: CA; data acquisition, analysis and interpretation, writing initial draft: HCG; data analysis, organization and interpretation, writing initial draft, revising and editing with intellectual content: TMA; data acquisition: TLC; revising draft with intellectual content: NM; concept and design of the study, funding acquisition, data organization and interpretation, revising and editing the draft with intellectual content: EJC. All authors approved the final manuscript. Conflicts of interest: The authors have no conflict of interest to disclose. Financial support: 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. Institutional review board statement: 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. Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication. Data sharing statement: Datasets analyzed during the current study are available from the corresponding author on reasonable request. Plagiarism check: Checked twice by iThenticate. Peer review: Externally peer reviewed. Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Open peer reviewers: Carolin Ruven, University of Hong Kong, School of Biomedical Sciences, China; Carolyn Tallon, Johns Hopkins University, USA.
Funding Information:
Funding: 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.
Publisher Copyright:
© 2019 BMJ Publishing Group. All rights reserved.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
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U2 - 10.4103/1673-5374.264471
DO - 10.4103/1673-5374.264471
M3 - Article
C2 - 31535662
AN - SCOPUS:85073359961
VL - 15
SP - 136
EP - 144
JO - Neural Regeneration Research
JF - Neural Regeneration Research
SN - 1673-5374
IS - 1
ER -