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J Neurosci. 2008 Dec 24;28(52):14107-20. doi: 10.1523/JNEUROSCI.2217-08.2008.

The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury.

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Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.


Chondroitinase ABC (ChABC) represents a promising therapeutic strategy for the treatment of spinal cord injury due to its potent effects on restoring function to spinal-injured adult mammals. However, there is limited mechanistic insight as to the underlying effects of ChABC treatment, where the effects are mediated, and which signaling pathways are involved in ChABC-mediated repair. Here we use a transgenic (YFP-H) mouse to demonstrate that cortical layer V projection neurons undergo severe atrophy 4 weeks after thoracic dorsal column injury and that ChABC is neuroprotective for these neurons after ICV infusion. ChABC also prevented cell atrophy after localized delivery to the spinal cord, suggesting a possible retrograde neuroprotective effect mediated at the injury site. Furthermore, neuroprotection of corticospinal cell somata coincided with increased axonal sprouting in the spinal cord. In addition, Western blot analysis of a number of kinases important in survival and growth signaling revealed a significant increase in phosphorylated ERK1 at the spinal injury site after in vivo ChABC treatment, indicating that activated ERK may play a role in downstream repair processes after ChABC treatment. Total forms of PKC and AKT were also elevated, indicating that modification of the glial scar by ChABC promotes long-lasting signaling changes at the lesion site. Thus, using the YFP-H mouse as a novel tool to study degenerative changes and repair after spinal cord injury we demonstrate, for the first time, that ChABC treatment regulates multiple signaling cascades at the injury site and exerts protective effects on axotomized corticospinal projection neurons.

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