title: A novel compound, denosomin, ameliorates spinal cord injury via axonal growth associated with astrocyte-secreted vimentin.
abstract: OBJECTIVE
  In the spinal cord injury (SCI) axon regeneration is inhibited by the glial scar, which contains reactive astrocytes that secrete inhibitory chondroitin sulphate proteoglycan (CSPG). We previously reported that a novel compound, denosomin, promotes axonal growth under degenerative conditions in cultured cortical neurons. In this study, we investigated the effects of denosomin on functional recovery in SCI mice and elucidated the mechanism though which denosomin induces axonal growth in the injured spinal cord.
  
  
  METHODS
  Denosomin was administered p.o. for 7 or 14 days to contusion mice. Behavioural evaluations and immunohistochemistry were done. Primary cultured cortical neurons and astrocytes were treated with denosomin to investigate the mechanism of axonal growth facilitation.
  
  
  RESULTS
  Denosomin improved hind limb motor dysfunction and axonal growth, especially in the 5-HT-positive tracts across the scar and increased the density of astrocytes. Denosomin increased astrocyte proliferation, inhibited astrocytic death and increased the expression and secretion of vimentin in cultured astrocytes. Furthermore, vimentin increased axonal outgrowth in cultured neurons, even in the presence of inhibitory CSPG. Denosomin increased the number of vimentin-expressing astrocytes inside glial scars of SCI mice, and 5-HT-positive axonal growth occurred in a vimentin-associated manner.
  
  
  CONCLUSIONS
  Denosomin increased the ratio of astrocytes that secrete vimentin as an axonal growth facilitator, which, we propose enhances axonal growth beyond the glial scar and promotes functional recovery in SCI mice. This study is the first to demonstrate this novel role of vimentin in SCI and drug-mediated modification of the inhibitory property of reactive astrocytes.
authors.affiliation: Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Kuboyama
authors.forename: Michiko
authors.initials: M
authors.lastname: Shigyo
authors.forename: Aiko
authors.initials: A
authors.lastname: Nagata
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuya
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tohda
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001369:Axons / Q000187:drug effects*; D002921:Cicatrix / Q000473:pathology / Q000517:prevention & control; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058630:Spinal Cord Regeneration / Q000187:drug effects*; D014746:Vimentin / Q000378:metabolism*
chemical_list: D014746:Vimentin; C543747:denosomin; D003687:Dehydroepiandrosterone