title: Irreversible changes occurring in long-term denervated Schwann cells affect delayed nerve repair.
abstract: OBJECTIVE Multiple factors may affect functional recovery after peripheral nerve injury, among them the lesion site and the interval between the injury and the surgical repair. When the nerve segment distal to the lesion site undergoes chronic degeneration, the ensuing regeneration (when allowed) is often poor. The aims of the current study were as follows: 1) to examine the expression changes of the neuregulin 1/ErbB system during long-term nerve degeneration; and 2) to investigate whether a chronically denervated distal nerve stump can sustain nerve regeneration of freshly axotomized axons. METHODS This study used a rat surgical model of delayed nerve repair consisting of a cross suture between the chronically degenerated median nerve distal stump and the freshly axotomized ulnar proximal stump. Before the suture, a segment of long-term degenerated median nerve stump was harvested for analysis. Functional, morphological, morphometric, and biomolecular analyses were performed. RESULTS The results showed that neuregulin 1 is highly downregulated after chronic degeneration, as well as some Schwann cell markers, demonstrating that these cells undergo atrophy, which was also confirmed by ultrastructural analysis. After delayed nerve repair, it was observed that chronic degeneration of the distal nerve stump compromises nerve regeneration in terms of functional recovery, as well as the number and size of regenerated myelinated fibers. Moreover, neuregulin 1 is still downregulated after delayed regeneration. CONCLUSIONS The poor outcome after delayed nerve regeneration might be explained by Schwann cell impairment and the consequent ineffective support for nerve regeneration. Understanding the molecular and biological changes occurring both in the chronically degenerating nerve and in the delayed nerve repair may be useful to the development of new strategies to promote nerve regeneration. The results suggest that neuregulin 1 has an important role in Schwann cell activity after denervation, indicating that its manipulation might be a good strategy for improving outcome after delayed nerve repair.
authors.affiliation: Department of Clinical and Biological Sciences.|Neuroscience Institute Cavalieri Ottolenghi, and.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ronchi
authors.affiliation: Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cillino
authors.affiliation: Department of Clinical and Biological Sciences.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gambarotta
authors.affiliation: Department of Clinical and Biological Sciences.
authors.forename: Benedetta Elena
authors.initials: BE
authors.lastname: Fornasari
authors.affiliation: Department of Clinical and Biological Sciences.|Neuroscience Institute Cavalieri Ottolenghi, and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Raimondo
authors.affiliation: Reconstructive Microsurgery, Centro Traumatologico Ortopedico Hospital, University of Torino; and.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Pugliese
authors.affiliation: Reconstructive Microsurgery, Centro Traumatologico Ortopedico Hospital, University of Torino; and.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tos
authors.affiliation: Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cordova
authors.affiliation: Plastic and Reconstructive Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Moschella
authors.affiliation: Department of Clinical and Biological Sciences.|Neuroscience Institute Cavalieri Ottolenghi, and.
authors.forename: Stefano
authors.initials: S
authors.lastname: Geuna
mesh_terms: D000818:Animals; D003714:Denervation; D005260:Female; D009410:Nerve Degeneration; D009416:Nerve Regeneration; D020890:Neuregulin-1 / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D012583:Schwann Cells; D013997:Time Factors
chemical_list: D020890:Neuregulin-1; C490580:Nrg1 protein, rat
keywords: ANKRD27 = ankyrin repeat domain 27; GAPDH = glyceraldehyde-3-phosphate-dehydrogenase; GFAP = glial fibrillary acidic protein; MBP = myelin basic protein; NRG1 = neuregulin 1; NRG1/ErbB system; NTF = N-terminal fragment; PCR = polymerase chain reaction; RICTOR = RPTOR independent companion of MTOR complex 2; RT = reverse transcription; delayed nerve repair; nerve degeneration; nerve regeneration; neuregulin 1; p75 = low-affinity nerve growth factor receptor; peripheral nerve; stereology