4-Aminopyridine (4-AP): A Single-Dose Diagnostic Agent to Diagnose Peripheral Nerve Continuity
John C Elfar, MD, FACS1, Anagha Gurjar, PhD1, Juan Estrada, PhD1, Marc Kaufman, PhD1 and M A Hassan Talukder, MBBS, PhD2, (1)The Pennsylvania State University, Hershey, PA, (2)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. Injured nerves may be stretched, crushed, or transected. Unfortunately, there is no early diagnostic test or tool available to differentiate a crushed nerve from a transected nerve. Advanced electro-diagnostic and imaging studies do not provide any diagnosis even after weeks or months of injury, and the treatment relies on 'watchful waiting' versus invasive exploration of the wound. Therefore, there is an unmet need for a diagnostic tool which could address these issues for early diagnosis and subsequent treatment strategies. 4-aminopyridine (4-AP) is a FDA-approved generic drug for symptomatic treatment of multiple sclerosis. We demonstrated that, at 1 day post-injury, a single dose of systemic 4-AP significantly can improve walking function in mice with crushed nerve injury but not in mice with transected nerves. While these findings indicate a role of 4-AP in identifying axonal continuity in awake/conscious animal, it is unknown whether this diagnostic criteria of 4-AP is applicable in unawake/sedated animal. We investigated the transient stimulatory effect of 4-AP on demyelinated axon for muscle contraction in fully sedated rats.
Materials & Methods: Sciatic nerve crush or transection injury was used to evaluate the effect of single dose 4-AP on muscle tension in anesthetized rats. A shielded stimulating electrode was placed under sciatic nerve and injury was performed distal to stimulating electrode.Sciatic nerve underwent a standardized crush injury or laceration injury. The triceps surae muscles were contracted for 10s at 40Hz, 0.1ms pulse, and a voltage two times above the motor threshold. The muscle tension was measured before injury, after crush or laceration, and at different time points after intraperitoneal injection of saline or 1mg/kg 4-AP.
Results: We found that both crush and transection injuries in sciatic nerve completely abolished muscle response to electrical stimulation). Single dose of 4-AP treatment significantly restored muscle responses to electrical stimulation in crush injury to a level 53% of pre-injury values within 30 min of 4-AP administration. However, 4AP treatment had no effect on muscle contraction after nerve transection.
Conclusion: We conclude that 4-AP could be a promising diagnostic agent in differentiating peripheral nerve injuries even in the unconscious patient, and this study provides the rationale for further investigation in the setting of peripheral neurotrauma where no alternative diagnostic tool is currently available.
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