Transdermal Application of 4-aminopyridine (4AP) Promotes Peripheral Nerve Injury Recovery: Improvements in Function, Axonal Degeneration, Myelination, Electrodiagnostic Parameters
John C Elfar, MD, FACS1, Andrew Clark, PhD2, Chia George Hsu, PhD2, Mark Noble, PhD2 and M A Hassan Talukder, MBBS, PhD3, (1)The Pennsylvania State University, Hershey, PA, (2)University of Rochester, Rochester, NY, (3)The Pennsylvania State University College of Medicine, Hershey, PA
Introduction:Traumatic peripheral nerve injury (TPNI) represents a major health problem that often leads to significant functional impairment and permanent disability. Despite the available modern diagnostic procedures and advanced microsurgical techniques, most patients with TPNIs do not regain full functional recovery. Therefore, there is an unmet need for new therapeutic strategies to promote functional recovery in TPNI patients. 4-aminopyridine (4AP), an FDA-approved drug for the treatment of multiple sclerosis, has been shown to improve neuromuscular function in patients with diverse demyelinating disorders. We demonstrated that systemic 4AP administration enhances global functional recovery of the affected limb, promotes remyelination and improves the nerve conduction velocity in a mouse model of TPNI. Although oral or injection routes are commonly used, the therapeutic benefits with transdermal delivery of drugs are well documented to provide a sustained circulating blood levels with enhanced patient compliance and importantly without the need for multiple daily oral dosing or injections. However, there is no data on the transdermal delivery of 4AP. Therefore, we asked whether 4AP could be used as a transdermal agent and what would be its effects on motor function and neuronal recovery after TPNI.
Materials & Methods:Mice were assigned to moderate sciatic nerve crush injury and the effects of acute and chronic treatments with transdermal 4AP (150 μg) and vehicle (DMSO) were investigated. Using Franz diffusion cells, the skin permeability of 4AP (40 mg/ml) in 0.5 mL water or DMSO was determined through mouse skin. Pharmacokinetic parameters of 4AP in serum were determined by HPLC method at specified time points after applying 7.5µL of 4AP in DMSO (10 mg/ml or 20mg/ml) to the lower back skin of anesthetized mice.
Results:4AP showed similar skin permeability coefficients in water and DMSO. Pharmacokinetic parameters of 4AP were linear, the maximum plasma 4AP concentrations were proportional to 4AP dose, and the time to maximum blood concentration was 60 min for both dosages. While a single dose of transdermal 4AP administration demonstrated rapid transient improvement in motor function, chronic transdermal 4AP 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.
Conclusions:Topical 4AP, absorbed through the skin, enhances in vivoglobal motor function recovery with decreased axonal degeneration, increased myelination and faster nerve conduction in axons. These findings provide direct evidence for the potential therapeutic use of transdermal 4AP in TPNI.
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