title: BDNF Induced by Treadmill Training Contributes to the Suppression of Spasticity and Allodynia After Spinal Cord Injury via Upregulation of KCC2.
abstract: BACKGROUND
  Spasticity and allodynia are major sequelae that affect the quality of life and daily activities of spinal cord injury (SCI) patients. Although rehabilitation ameliorates spasticity and allodynia, the molecular mechanisms involved in these processes remain elusive.
  
  
  OBJECTIVE
  To investigate the molecular mechanisms by which rehabilitation ameliorates spasticity and allodynia after SCI in rats.
  
  
  METHODS
  The expression levels of brain-derived neurotrophic factor (BDNF) and potassium-chloride cotransporter-2 (KCC2), as well as the localization of KCC2, were examined in the lumbar enlargements of untrained and treadmill-trained thoracic SCI model rats. Spasticity and allodynia were determined via behavioral and electrophysiological analyses. The effects of BDNF on spasticity, allodynia, and KCC2 activation were determined by inhibition of BDNF signaling via intrathecal administration of TrkB-IgG. The effects of SCI and training on the expression levels of functional phospholipase C-γ in the lumbar enlargement were also examined.
  
  
  RESULTS
  Treadmill training after SCI upregulated endogenous BDNF expression and posttranslational modification of KCC2 in the lumbar enlargement significantly. There were also significant correlations between increased KCC2 expression and ameliorated spasticity and allodynia. Administration of TrkB-IgG abrogated the training-induced upregulation of KCC2 and beneficial effects on spasticity and allodynia. The expression level of functional phospholipase C-γ was reduced significantly after SCI, which may have contributed to the change in the function of BDNF, whereby it did not trigger short-term downregulation or induce long-term upregulation of KCC2 expression secondary to training.
  
  
  CONCLUSIONS
  BDNF-mediated restoration of KCC2 expression underlies the suppression of spasticity and allodynia caused by rehabilitation.
authors.affiliation: Department of Rehabilitation Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Syoichi
authors.initials: S
authors.lastname: Tashiro
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shinozaki
authors.affiliation: Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mukaino
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: François
authors.initials: F
authors.lastname: Renault-Mihara
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Rehabilitation Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Meigen
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D005080:Exercise Test; D005260:Female; D006930:Hyperalgesia / Q000209:etiology / Q000534:rehabilitation*; D007074:Immunoglobulin G / Q000627:therapeutic use; D008124:Locomotion; D009128:Muscle Spasticity / Q000209:etiology / Q000534:rehabilitation*; D009474:Neurons / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D026741:Physical Therapy Modalities; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000276:immunology; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D018709:Statistics, Nonparametric; D027981:Symporters / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology*; D000096922:K Cl- Cotransporters
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015740:Calcitonin Gene-Related Peptide; D007074:Immunoglobulin G; D051966:Phospholipase C gamma; D020813:Receptor, trkB; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: KCC2; allodynia; brain-derived neurotrophic factor; phospholipase C; spasticity; spinal cord injury