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J Reconstr Microsurg
DOI: 10.1055/a-2540-0786
Original Article

Effects of 4-aminopyridine as an Adjuvant Therapy Following Peripheral Nerve Repair in an Animal Model of Nerve Transection Injury

Jung Il Lee 
1   Department of Orthopedic Surgery, Korea University College of Medicine, Seoul, South Korea
,
Dong Whan Kim
1   Department of Orthopedic Surgery, Korea University College of Medicine, Seoul, South Korea
,
Jong Woong Park
1   Department of Orthopedic Surgery, Korea University College of Medicine, Seoul, South Korea
,
Duk Hee Lee
2   Department of Emergency Medicine, Ewha Women's University Mokdong Hospital, Seoul, South Korea
› Author Affiliations
Funding This work was supported by the Korea University Guro Hospital (KOREA RESEARCH-DRIVEN HOSPITAL) and a grant funded by Korea University Medicine (K2314941). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (RS-2024-00336486) (both to J.I.L).
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Abstract

Background

Peripheral nerve repair is considered the gold standard treatment for complete nerve transection injuries, yet achieving satisfactory functional recovery remains challenging due to muscle atrophy during the time required for axonal regeneration. This study investigated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, on neural and muscular recovery.

Methods

Following complete transection of the right sciatic nerve, 40 mice underwent end-to-end nerve repair using microscopic epineural sutures and were randomly assigned to either the control or 4-AP groups immediately after surgery (n = 20 per group). The experimental animals were administered intraperitoneal injections of 200 μL normal saline or soluble 4-AP at a dose of 10 μg daily. The sciatic functional index (SFI) and nerve conduction studies were measured until 12 weeks postoperatively. Morphological analyses of nerve and muscle, and Western blotting for proteins associated with muscle atrophy were performed at 3 and 12 weeks after surgery.

Results

There were no significant differences in the SFI between the two groups. Nerve conduction study showed that 4-AP treatment increased the compound muscle action potential and decreased latency. A histomorphometric study showed that 4-AP treatment increased myelin thickness, G-ratio (axonal diameter/axoglial diameter on cross-sectioned nerve), cross-sectional area of myofibrils, and minimal Feret diameter of myofibrils. Additionally, expression levels of FoxO3 and mTORC1 were lower in the 4-AP treated mice, while myogenin expression levels showed no significant difference between the groups.

Conclusion

4-AP treatment promotes myelination and prevents denervation-induced muscle atrophy after neurorrhaphy. These findings suggest that 4-AP may be a promising candidate for clinical consideration as an adjuvant therapy following nerve repair for transection injuries.

Keywords

peripheral nerve - nerve injury - nerve regeneration - muscle atrophy - nerve repair - neurorrhaphy - 4-aminopyridine - 4-AP

Author Contributions

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. J.I. Lee: conceptualization, methodology, investigation, writing—original draft, and funding acquisition; D.W. Kim: investigation; J.W. Park: review & editing and supervision; D.H. Lee: formal analysis and writing—review & editing.


Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.




Publication History

Received: 11 September 2024

Accepted: 26 January 2025

Article published online:
07 March 2025

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