TrkA inhibitor promotes motor functional regeneration of recurrent laryngeal nerve by suppression of sensory nerve regeneration

Hiroshi Suzuki,Masayuki Tomifuji,Toshiyasu Matsui,Yasushi Satoh,Yasushi Kobayashi,Kosuke Uno,Akihiro Shiotani,Taku Yamashita,Yuya Tanaka,Koji Araki

doi:10.1038/s41598-020-72288-w

Abstract

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.

Highlights

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication
In this study, using a left RLN axotomy model that we had previously reported[25], we investigated whether treatment with TrkA inhibitors improved vocal fold function
With the aim of improving misdirected regeneration among motor and sensory fibers, we investigated whether TrkA inhibitors could improve vocal fold function as a basis for polyglycolic acid (PGA)-Collagen tube treatment in an RLN axotomy model

Summary

Introduction

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. The causes of vocal fold immobility following RLN injury include motor neuron death in the nucleus ambiguus, degeneration and poor regeneration of nerve fibres and motor endplates, laryngeal muscle atrophy, and misdirected r egeneration[8,9,10,11]. Misdirected regeneration among the motor fibers that control these muscles precludes correct closure and opening of the glottis in response to accurate commands, resulting in vocal fold immobility and paradoxical movement. Misdirected nerves can be avoided by eliminating misdirected regeneration of (1) abductor and adductor motor fibers, and (2) motor fibers and sensory/automatic fibers

Methods

Results

Conclusion