Neurotrophin 3 Improves Delayed Reconstruction of Sensory Pathways After Cervical Dorsal Root Injury

Abstract

Spinal root avulsion, or section, results in devastating functional sequels. Whereas reconstruction of motor pathways based on neurotization can reduce motor deficit, associated permanent limb anesthesia limits expected benefit. Sensory pathway reconstruction after dorsal root injury is limited by the inability of re-growing central sensory axons to enter the spinal cord through an injured root. To provide evidence for the reconnection of C7 DRG neurons with the central nervous system (CNS) after experimental section of the C7 dorsal root in adult rats. We assessed a new reconstruction strategy in adult rats 9 weeks after transection of C6 and C7 dorsal roots. Re-growing C7 central sensory axons were redirected to the noninjured C5 dorsal root through a nerve graft by end-to-side anastomosis that did not alter the C5 conduction properties. In a subgroup of rats, surgical reconstruction was combined with lentivirus-mediated gene transfer to the nerve graft in order to overexpress neurotrophin 3 (NT-3), a neurotrophic factor that stimulates sensory axon regeneration. Four months after reconstruction, recording of sensory evoked potentials and fluorescent tracer transport showed electrical and physical reconnection of the C7 dorsal root ganglion neurons to the spinal cord through the reconstructed pathway. Sensory perception recovery predominated on proprioception. Axonal regrowth and perception were improved when the nerve graft overexpressed neurotrophin-3 at the time of transplantation. Neurotrophin-3 overexpression did not persist 4 months after transplantation. Efficient and functional reconnection of dorsal root ganglion neurons to the spinal cord can be achieved in rats several weeks after cervical dorsal root injury. Surgical repair of sensory pathways could be considered in combination with motor nerve neurotization to treat persisting severe upper limb disability in humans.