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Objective: Poor functional recovery after peripheral nerve injury is generally attributed to irreversible target atrophy. In rats, we addressed the functional outcomes of prolonged neuronal separation from targets (chronic axotomy for up to 1 year) and atrophy of Schwann cells (SCs) in distal nerve stumps, and whether electrical stimulation (ES) accelerates axon regeneration. In carpal tunnel syndrome (CTS) patients with severe axon degeneration and release surgery, we asked whether ES accelerates muscle reinnervation. Methods: Reinnervated motor unit (MUs) and regenerating neuron numbers were counted electrophysiologically and with dye-labeling after chronic axotomy, chronic SC denervation and after immediate nerve repair with and without trains of 20 Hz ES for 1 hour to 2 weeks in rats and in CTS patients. Results: Chronic axotomy reduced regenerative capacity to 67% and was alleviated by exogenous growth factors. Reduced regeneration to ∼10% by SC denervation atrophy was ameliorated by forskolin and transforming growth factor-β SC reactivation. ES (1 h) accelerated axon outgrowth across the suture site in association with elevated neuronal neurotrophic factor and receptors and in patients, promoted the full reinnervation of thenar muscles in contrast to a non-significant increase in MU numbers in the control group. Discussion: The rate limiting process of axon outgrowth, progressive deterioration of both neuronal growth capacity and SC support, but not irreversible target atrophy, account for observed poor functional recovery after nerve injury. Brief ES accelerates axon outgrowth and target muscle reinnervation in animals and humans, opening the way to future clinical application to promote functional recovery. [ABSTRACT FROM AUTHOR]

Schwann cell phenotype is classified as either myelinating or nonmyelinating. Additional phenotypic specialization is suggested, however, by the preferential reinnervation of muscle pathways by motoneurons. To explore potential differences in growth factor expression between sensory and motor nerve, grafts of cutaneous nerve or ventral root were denervated, reinnervated with cutaneous axons, or reinnervated with motor axons. Competitive reverse transcription-PCR was performed on normal cutaneous nerve and ventral root and on graft preparations 5, 15, and 30 d after surgery. mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1 was expressed vigorously by denervated and reinnervated cutaneous nerve but minimally by ventral root. In contrast, mRNA for pleiotrophin (PTN) and glial cell line-derived neurotrophic factor was upregulated to a greater degree in ventral root. ELISA confirmed that NGF and BDNF protein were significantly more abundant in denervated cutaneous nerve than in denervated ventral root, but that PTN protein was more abundant in denervated ventral root. The motor phenotype was not immutable and could be modified toward the sensory phenotype by prolonged reinnervation of ventral root by cutaneous axons. Retrograde labeling to quantify regenerating neurons demonstrated that cutaneous nerve preferentially supported cutaneous axon regeneration, whereas ventral root preferentially supported motor axon regeneration. Schwann cells thus express distinct sensory and motor phenotypes that are associated with the support of regeneration in a phenotype-specific manner. These findings suggest that current techniques of bridging gaps in motor and mixed nerve with cutaneous graft could be improved by matching axon and Schwann cell properties. [ABSTRACT FROM AUTHOR]