Brain Advance Access originally published online on May 19, 2009
Brain 2009 132(6):1449-1462; doi:10.1093/brain/awp128
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Polysialic acid glycomimetics promote myelination and functional recovery after peripheral nerve injury in mice
1 Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 85, D-20246 Hamburg, Germany 2 Department of Otorhinolaryngology, Friedrich-Schiller-University Jena, Lessingstrasse 2, D-07740 Jena, Germany 3 W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA 4 Center for Neuroscience, Shantou University Medical College, Shantou 515041, China
Correspondence to: Prof. Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 85, D-20246 Hamburg, Germany E-mail: Schachner{at}Biology.Rutgers.Edu
2,8 Polysialic acid (PSA) is a carbohydrate attached to the glycoprotein backbone of the neural cell adhesion molecule (NCAM) and implicated in nervous system development and repair. Here, we investigated whether PSA can improve functional recovery after peripheral nerve lesion in adult mice. We applied a functional PSA mimicking peptide or a control peptide in a polyethylene cuff used to surgically reconnect the severed stumps of the femoral nerve before it bifurcates into the motor and sensory branches. Using video-based motion analysis to monitor motor recovery over a 3 month postoperative period, we observed a better functional outcome in the PSA mimetic-treated than in control mice receiving a control peptide or phosphate buffered saline. Retrograde tracing of regenerated motoneurons and morphometric analyses showed that motoneuron survival, motoneuron soma size and axonal diameters were not affected by treatment with the PSA mimetic. However, remyelination of regenerated axons distal to the injury site was considerably improved by the PSA mimetic indicating that effects on Schwann cells in the denervated nerve may underlie the functional effects seen in motor recovery. In line with this notion was the observation that the PSA mimetic enhanced the elongation of Schwann cell processes and Schwann cell proliferation in vitro, when compared with the control peptide. Moreover, Schwann cell proliferation in vivo was enhanced in both motor and sensory branches of the femoral nerve by application of the PSA mimetic. These effects were likely mediated by NCAM through its interaction with the fibroblast growth factor receptor (FGFR), since they were not observed when the PSA mimetic was applied to NCAM-deficient Schwann cells, and since application of two different FGFR inhibitors reduced process elongation from Schwann cells in vitro. Our results indicate the potential of PSA mimetics as therapeutic agents promoting motor recovery and myelination after peripheral nerve injury.
Key Words: PSA mimetic; functional recovery; myelination; Schwann cells
Abbreviations:
DRG, dorsal root ganglia; FBA, foot-base angle; FGFR, fibroblast growth factor receptor; HNK, human natural killer; HTA, heels-tail angle; NCAM, neural cell adhesion molecule; PMR, Preferential motor reinnervation; PSA, 2,8 polysialic acid
Received November 12, 2008. Revised March 13, 2009. Accepted March 22, 2009.