title: Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition.
abstract: BACKGROUND
  Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the "rewiring" of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment.
  
  
  RESULTS
  Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles).
  
  
  CONCLUSIONS
  This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Kaneko
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sano
authors.forename: Miho
authors.initials: M
authors.lastname: Maeda
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kishino
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mukaino
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Meigen
authors.initials: M
authors.lastname: Liu
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006614:Hindlimb / Q000503:physiopathology; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D010805:Physical Conditioning, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012828:Silicones; D013116:Spinal Cord / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D044004:Xanthones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D040121:Semaphorin-3A; D012828:Silicones; D044004:Xanthones; C086647:vinaxanthone