title: Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection.
abstract: Chondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose ChABC (1 U) in the acute stage of SCI promoted axonal regrowth and functional recovery. In this study, high-dose ChABC (50 U) introduced via intrathecal delivery induced subarachnoid hemorrhage and death within 48 h. However, most SCI patients are treated in the sub-acute or chronic stages, when the dense glial scar has formed and is minimally digested by intrathecal delivery of ChABC at the injury site. The present study investigated whether intraparenchymal delivery of ChABC in the sub-acute stage of complete spinal cord transection would promote axonal outgrowth and improve functional recovery. We observed no functional recovery following the low-dose ChABC (1 U or 5 U) treatments. Furthermore, animals treated with high-dose ChABC (50 U or 100 U) showed decreased CSPGs levels. The extent and area of the lesion were also dramatically decreased after ChABC treatment. The outgrowth of the regenerating axons was significantly increased, and some partially crossed the lesion site in the ChABC-treated groups. In addition, retrograde Fluoro-Gold (FG) labeling showed that the outgrowing axons could cross the lesion site and reach several brain stem nuclei involved in sensory and motor functions. The Basso, Beattie and Bresnahan (BBB) open field locomotor scores revealed that the ChABC treatment significantly improved functional recovery compared to the control group at eight weeks after treatment. Our study demonstrates that high-dose ChABC treatment in the sub-acute stage of SCI effectively improves glial scar digestion by reducing the lesion size and increasing axonal regrowth to the related functional nuclei, which promotes locomotor recovery. Thus, our results will aid in the treatment of spinal cord injury.
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chu-Hsun
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors.forename: Chi-Te
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan.
authors.forename: Meng-Jen
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: May-Jywan
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Huang
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Huang
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Graduate Institute of Veterinary Pathobiology, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Yi-Lo
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ching-Jung
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Center for Neural Regeneration, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Center for Neural Regeneration, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Henrich
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001369:Axons; D001933:Brain Stem / Q000473:pathology; D019765:Chondroitin ABC Lyase / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007278:Injections, Spinal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: D019765:Chondroitin ABC Lyase