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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
› Institutsangaben 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.




Publikationsverlauf

Eingereicht: 11. September 2024

Angenommen: 26. Januar 2025

Artikel online veröffentlicht:
07. März 2025

© 2025. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Griffin JW, Hogan MV, Chhabra AB, Deal DN. Peripheral nerve repair and reconstruction. J Bone Joint Surg Am 2013; 95 (23) 2144-2151
    CrossrefPubMedSuche in Google Scholar
  • 2 Kim DH, Kam AC, Chandika P, Tiel RL, Kline DG. Surgical management and outcomes in patients with median nerve lesions. J Neurosurg 2001; 95 (04) 584-594
    CrossrefPubMedSuche in Google Scholar
  • 3 Kim DH, Han K, Tiel RL, Murovic JA, Kline DG. Surgical outcomes of 654 ulnar nerve lesions. J Neurosurg 2003; 98 (05) 993-1004
    CrossrefPubMedSuche in Google Scholar
  • 4 Brushart TM. Nerve Repair: Oxford University Press; 2011
    PubMed
  • 5 Mackinnon SE, Yee A. Nerve Surgery. New York: Thieme; 2015
    PubMed
  • 6 Isaacs J. Major peripheral nerve injuries. Hand Clin 2013; 29 (03) 371-382
    CrossrefPubMedSuche in Google Scholar
  • 7 Grinsell D, Keating CP. Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. BioMed Res Int 2014; 2014: 698256
    CrossrefPubMedSuche in Google Scholar
  • 8 Modrak M, Talukder MAH, Gurgenashvili K, Noble M, Elfar JC. Peripheral nerve injury and myelination: potential therapeutic strategies. J Neurosci Res 2020; 98 (05) 780-795
    CrossrefPubMedSuche in Google Scholar
  • 9 Hussain G, Wang J, Rasul A. et al. Current status of therapeutic approaches against peripheral nerve injuries: a detailed story from injury to recovery. Int J Biol Sci 2020; 16 (01) 116-134
    CrossrefPubMedSuche in Google Scholar
  • 10 Fernandez L, Komatsu DE, Gurevich M, Hurst LC. Emerging strategies on adjuvant therapies for nerve recovery. J Hand Surg Am 2018; 43 (04) 368-373
    CrossrefPubMedSuche in Google Scholar
  • 11 Chan KM, Gordon T, Zochodne DW, Power HA. Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets. Exp Neurol 2014; 261: 826-835
    CrossrefPubMedSuche in Google Scholar
  • 12 Tseng KC, Li H, Clark A. et al. 4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. EMBO Mol Med 2016; 8 (12) 1409-1420
    CrossrefPubMedSuche in Google Scholar
  • 13 Clark AR, Hsu CG, Talukder MAH, Noble M, Elfar JC. Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice. Neural Regen Res 2020; 15 (01) 136-144
    CrossrefPubMedSuche in Google Scholar
  • 14 Toraman M, Külekçi Öztürk S, Uslu Coşkun B, Güneş P. The effects of 4-aminopyridine and methylprednisolone on recovery of the facial nerve crush injury. Eur Arch Otorhinolaryngol 2021; 278 (08) 3057-3063
    CrossrefPubMedSuche in Google Scholar
  • 15 Yue L, Talukder MAH, Gurjar A. et al. 4-Aminopyridine attenuates muscle atrophy after sciatic nerve crush injury in mice. Muscle Nerve 2019; 60 (02) 192-201
    CrossrefPubMedSuche in Google Scholar
  • 16 Hsu CG, Talukder MAH, Yue L, Turpin LC, Noble M, Elfar JC. Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice. Neural Regen Res 2020; 15 (11) 2098-2107
    CrossrefPubMedSuche in Google Scholar
  • 17 Lee DH, You J, Jung JW, Park JW, Lee JI. Comparison between normal and reverse orientation of graft in functional and histomorphological outcomes after autologous nerve grafting: an experimental study in the mouse model. Microsurgery 2021; 41 (07) 645-654
    CrossrefPubMedSuche in Google Scholar
  • 18 Bain JR, Mackinnon SE, Hunter DA. Functional evaluation of complete sciatic, peroneal, and posterior tibial nerve lesions in the rat. Plast Reconstr Surg 1989; 83 (01) 129-138
    CrossrefPubMedSuche in Google Scholar
  • 19 Lee JI, Park JW, Lee KJ, Lee DH. Clemastine improves electrophysiologic and histomorphometric changes through promoting myelin repair in a murine model of compression neuropathy. Sci Rep 2021; 11 (01) 20886
    CrossrefPubMedSuche in Google Scholar
  • 20 Judge SI, Bever Jr CT. Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 2006; 111 (01) 224-259
    CrossrefPubMedSuche in Google Scholar
  • 21 Jensen HB, Ravnborg M, Dalgas U, Stenager E. 4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review. Ther Adv Neurol Disord 2014; 7 (02) 97-113
    CrossrefPubMedSuche in Google Scholar
  • 22 Ghorbanpour S, Rahimibarghani S, Rohani S, Rastkar M, Ghajarzadeh M. Fampridine for gait imbalance in patients with multiple sclerosis (MS): a systematic review and meta-analysis. Neurol Sci 2023; 44 (09) 3059-3069
    CrossrefPubMedSuche in Google Scholar
  • 23 Govindappa PK, Jagadeeshaprasad MG, Tortora P, Talukder MAH, Elfar JC. Effects of 4-aminopyridine on combined nerve and muscle injury and bone loss. J Hand Surg Am 2023; 48 (08) 831.e1-831.e9
    CrossrefPubMedSuche in Google Scholar
  • 24 Lee JI, Talukder MAH, Karuman Z. et al. Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice: effects of 4-aminopyridine. Neural Regen Res 2023; 18 (02) 439-444
    CrossrefPubMedSuche in Google Scholar
  • 25 Lee SK, Wolfe SW. Peripheral nerve injury and repair. J Am Acad Orthop Surg 2000; 8 (04) 243-252
    CrossrefPubMedSuche in Google Scholar
  • 26 Yin L, Li N, Jia W. et al. Skeletal muscle atrophy: from mechanisms to treatments. Pharmacol Res 2021; 172: 105807
    CrossrefPubMedSuche in Google Scholar
  • 27 Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 2013; 6 (01) 25-39
    CrossrefPubMedSuche in Google Scholar
  • 28 Glass DJ. Signaling pathways perturbing muscle mass. Curr Opin Clin Nutr Metab Care 2010; 13 (03) 225-229
    CrossrefPubMedSuche in Google Scholar
  • 29 Bodine SC, Stitt TN, Gonzalez M. et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001; 3 (11) 1014-1019
    CrossrefPubMedSuche in Google Scholar
  • 30 MacDonald EM, Andres-Mateos E, Mejias R. et al. Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition. Dis Model Mech 2014; 7 (04) 471-481
    PubMedSuche in Google Scholar
  • 31 Beharry AW, Sandesara PB, Roberts BM, Ferreira LF, Senf SM, Judge AR. HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy. J Cell Sci 2014; 127 (Pt 7): 1441-1453
    PubMedSuche in Google Scholar
  • 32 Sandri M, Sandri C, Gilbert A. et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004; 117 (03) 399-412
    CrossrefPubMedSuche in Google Scholar
  • 33 Moresi V, Williams AH, Meadows E. et al. Myogenin and class II HDACs control neurogenic muscle atrophy by inducing E3 ubiquitin ligases. Cell 2010; 143 (01) 35-45
    CrossrefPubMedSuche in Google Scholar
  • 34 Dellon AL, Mackinnon SE. Sciatic nerve regeneration in the rat. Validity of walking track assessment in the presence of chronic contractures. Microsurgery 1989; 10 (03) 220-225
    CrossrefPubMedSuche in Google Scholar
  • 35 Munro CA, Szalai JP, Mackinnon SE, Midha R. Lack of association between outcome measures of nerve regeneration. Muscle Nerve 1998; 21 (08) 1095-1097
    CrossrefPubMedSuche in Google Scholar
  • 36 Lee JY, Giusti G, Wang H, Friedrich PF, Bishop AT, Shin AY. Functional evaluation in the rat sciatic nerve defect model: a comparison of the sciatic functional index, ankle angles, and isometric tetanic force. Plast Reconstr Surg 2013; 132 (05) 1173-1180
    CrossrefPubMedSuche in Google Scholar
  • 37 Tapp M, Wenzinger E, Tarabishy S, Ricci J, Herrera FA. The epidemiology of upper extremity nerve injuries and associated cost in the US emergency departments. Ann Plast Surg 2019; 83 (06) 676-680
    CrossrefPubMedSuche in Google Scholar