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Novel Rat Forelimb Model Optimizes Measurement of Functional Recovery after Chronic Denervation of Peripheral Nerves
Amy Quan, MPH, Joseph Lopez, MD MBA, Joshua Budihardjo, BS, Sara Mermulla, MBBS, Tariq Jawadi, BS1; Howard D Wang, MD; Ahmet Hoke, MD PhD; Sami Tuffaha, MD; WP Andrew Lee, MD; Gerald Brandacher, MD
Johns Hopkins University School of Medicine, Baltimore, MD
Introduction: Chronic denervation of upper and lower extremity motor nerves causes significant damage to peripheral nerves: Schwann cells undergo apoptosis, axonal basal laminae deteriorate, and target muscles atrophy. Thus, chronic denervation of peripheral nerves results in decreased nerve regeneration potential and negatively impacts clinical outcomes after extremity nerve trauma. Although the cellular and molecular effects of chronic denervation on peripheral nerve regeneration are well understood, previous studies have failed to correlate these results to behavioral functional results. To address this problem, we have developed a novel murine, upper extremity nerve injury model that optimizes measurement of functional recovery after chronic denervation injury.
Methods: We developed a forelimb chronic denervation model in which the median nerve was transected at the mid-humerus level and left in discontinuity for 0, 8 or 12 weeks. After the period of chronic denervation was complete, the distal median nerve stump was co-apted to the proximal end of a freshly axotomized ulnar nerve. Group 1 rats underwent 8 weeks of chronic denervation (n= 8); Group 2 rats underwent 12 weeks of chronic denervation (n=8); Group 3 rats (positive control) underwent immediate neurorrhaphy of the ulnar and median nerves (n = 8); and Group 4 rats (naïve control) did not undergo any surgical procedure (n = 8). Functional recovery was tested weekly by measuring grip strength using a force transducer, scoring the injured forelimb during feeding, and recording compound muscle action potentials (CMAPs) in the abductor pollicis brevis muscle of the injured limb. Animals were sacrificed at 14 weeks after ulnar-median neurorrhaphy for assessment of axonal regeneration and degree of muscle atrophy.
Results: Fourteen weeks after ulnar-median neurorrhaphy, Group 3 rats demonstrated significant functional recovery, as compared with Group 1. Group 3 rats demonstrated greater grip strength than Group 1 (2.2 ± 0.3 Newtons vs. 1.0 ± 0.1 Newtons, P=0.001), improved feeding (score of 7.3 ± 0.05 vs. 6.0 ± 0.04, P<0.0001), and greater CMAPs (1.7 ± 0.07 millivolts vs. 0.5 ± 0.04 millivolts, P=0.0001). Furthermore, forelimb flexor muscle weights were significantly different between Group 3 and 1 (0.82 grams vs. 0.53 grams; P<0.00001). Results for Group 2 and 4 animals are pending.
Conclusions: This novel forelimb chronic denervation model provides the first translatable animal model to assess functional recovery after peripheral nerve chronic denervation injury. This model provides a reliable model to assess future therapeutics aimed at augmenting extremity function following chronic denervation injury of peripheral nerves.
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