title: Delayed treatment with chondroitinase ABC reverses chronic atrophy of rubrospinal neurons following spinal cord injury.
abstract: Degradation of extracellular matrix chondroitin sulphate proteoglycans (CSPGs) using Chondroitinase ABC (ChABC) is a promising strategy for the treatment of spinal cord injury, with potent effects on promoting functional recovery and anatomical repair in spinal injured animals. We have previously demonstrated that ChABC treatment prevents atrophy of corticospinal projection neurons following spinal injury in adult YFP-H mice. Here, we investigate whether ChABC-mediated repair of the cell body extends to rubrospinal projection neurons (RSNs), whether neuroprotective effects can be sustained long-term and importantly, whether delayed treatment with ChABC can reverse chronic atrophy. Adult YFP-H mice underwent unilateral rubrospinal tract transection and were treated with ChABC or a control enzyme, delivered either acutely post-injury or after a one month delay. Eight weeks following injury and control treatment, RSNs in the injured red nucleus, identified by YFP label and NeuN immunoreactivity, showed severe atrophy, with ~40% loss of mean cell area compared to uninjured neurons in the contralateral red nucleus. Both acute and delayed treatment with ChABC promoted a significant rescue of injured RSNs, restoring cell area to ~80% and ~70%, respectively, of that in uninjured neurons. Thus, we demonstrate for the first time that CSPG degradation in the injured spinal cord not only promotes sustained rescue of cell atrophy when delivered acutely but can also reverse chronic atrophy in descending projection neurons. Thus, modulation of the extracellular matrix can mediate neuroprotective effects both early and late after spinal cord injury.
authors.affiliation: King's College London, Neurorestoration Group, Wolfson Centre for Age Related Diseases, Wolfson Wing, Hodgkin Building, Guy's Campus, London Bridge, London SE1 1UL, UK. lucy.m.carter@kcl.ac.uk
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Carter
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Bradbury
mesh_terms: D000818:Animals; D001284:Atrophy / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002574:Cervical Vertebrae; D019765:Chondroitin ABC Lyase / Q000008:administration & dosage*; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012012:Red Nucleus / Q000187:drug effects / Q000201:enzymology*; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019765:Chondroitin ABC Lyase