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

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 ¼ 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. © 2025. Thieme. All rights reserved.