Experimental strategies to promote functional recovery after peripheral nerve injuries

TLDR

Peripheral nerve regeneration relies on Schwann cells, unlike oligodendrocytes in the CNS, yet it is often mistakenly believed to always restore function. The study aims to evaluate whether a brief 20 Hz electrical stimulation can enhance axon regeneration across a surgical gap after nerve repair. The authors examine the impact of chronic axotomy and chronic denervation on motoneuron regeneration and test brief 20 Hz electrical stimulation to counteract these effects. Low‑dose BDNF, glial‑derived neurotrophic factors, FK506, and TGF‑β promote axonal regeneration after chronic axotomy, while high‑dose BDNF via p75 inhibits regeneration and chronic denervation severely limits regeneration but permits surviving axons to form enlarged motor units.

Abstract

Abstract The capacity of Schwann cells (SCs) in the peripheral nervous system to support axonal regeneration, in contrast to the oligodendrocytes in the central nervous system, has led to the misconception that peripheral nerve regeneration always restores function. Here, we consider how prolonged periods of time that injured neurons remain without targets during axonal regeneration (chronic axotomy) and that SCs in the distal nerve stumps remain chronically denervated (chronic denervation) progressively reduce the number of motoneurons that regenerate their axons. We demonstrate the effectiveness of low‐dose, brain‐derived neurotrophic and glial‐derived neurotrophic factors to counteract the effects of chronic axotomy in promoting axonal regeneration. High‐dose brain‐derived neurotrophic factor (BDNF) on the other hand, acting through the p75 receptor, inhibits axonal regeneration and may be a factor in stopping regenerating axons from forming neuromuscular connections in skeletal muscle. The immunophilin, FK506, is also effective in promoting axonal regeneration after chronic axotomy. Chronic denervation of SCs (>1 month) severely deters axonal regeneration, although the few motor axons that do regenerate to reinnervate muscles become myelinated and form enlarged motor units in the reinnervated muscles. We found that in vitro incubation of chronically denervated SCs with transforming growth factor‐β re‐established their growth‐supportive phenotype in vivo, consistent with the idea that the interaction between invading macrophages and denervated SCs during Wallerian degeneration is essential to sustain axonal regeneration by promoting the growth‐supportive SC phenotype. Finally, we consider the effectiveness of a brief period of 20 Hz electrical stimulation in promoting the regeneration of axons across the surgical gap after nerve repair.