Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice
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 condu...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2020-01-01
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| Series: | Neural Regeneration Research |
| Subjects: | |
| Online Access: | http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=1;spage=136;epage=144;aulast=Clark |
| _version_ | 1811222144571408384 |
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| author | Andrew R Clark Chia George Hsu M A Hassan Talukder Mark Noble John C Elfar |
| author_facet | Andrew R Clark Chia George Hsu M A Hassan Talukder Mark Noble John C Elfar |
| author_sort | Andrew R Clark |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T08:11:31Z |
| format | Article |
| id | doaj.art-befefddb0b4a46238df64b8bb2e6169a |
| institution | Directory Open Access Journal |
| issn | 1673-5374 |
| language | English |
| last_indexed | 2024-04-12T08:11:31Z |
| publishDate | 2020-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj.art-befefddb0b4a46238df64b8bb2e6169a2022-12-22T03:40:57ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53742020-01-0115113614410.4103/1673-5374.264471Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in miceAndrew R ClarkChia George HsuM A Hassan TalukderMark NobleJohn C ElfarOral 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.http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=1;spage=136;epage=144;aulast=Clark4-aminopyridine; electron microscopy; functional recovery; nerve conduction velocity; peripheral nerve injury; pharmacokinetics; transdermal administration |
| spellingShingle | Andrew R Clark Chia George Hsu M A Hassan Talukder Mark Noble John C Elfar Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice Neural Regeneration Research 4-aminopyridine; electron microscopy; functional recovery; nerve conduction velocity; peripheral nerve injury; pharmacokinetics; transdermal administration |
| title | Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice |
| title_full | Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice |
| title_fullStr | Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice |
| title_full_unstemmed | Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice |
| title_short | Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice |
| title_sort | transdermal delivery of 4 aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice |
| topic | 4-aminopyridine; electron microscopy; functional recovery; nerve conduction velocity; peripheral nerve injury; pharmacokinetics; transdermal administration |
| url | http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=1;spage=136;epage=144;aulast=Clark |
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