title: Tumor necrosis factor-α antagonist reduces apoptosis of neurons and oligodendroglia in rat spinal cord injury.
abstract: METHODS
  To examine the effects of a tumor necrosis factor (TNF)-α antagonist (etanercept) on rat spinal cord injury and identify a possible mechanism for its action.
  
  
  OBJECTIVE
  To elucidate the contribution of etanercept to the pathologic cascade in spinal cord injury and its possible suppression of neuronal and oligodendroglial apoptosis.
  
  
  BACKGROUND
  Etanercept has been recently used successfully for treatment of inflammatory disorders. However, only a few studies have examined its role in suppressing neuronal and oligodendroglial apoptosis in spinal cord injury.
  
  
  METHODS
  Etanercept or saline (control) was administered by intraperitoneal injection 1 hour after thoracic spinal cord injury in rats. The expressions and localizations of TNF-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) were examined by immunoblot and immunohistochemical analyses. Spinal cord tissue damage between saline- and etanercept-treated groups was also compared after hematoxylin-eosin and luxol fast blue (LFB) staining. The Basso-Beattie-Bresnahan (BBB) scale was used to evaluate rat locomotor function after etanercept administration. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells were counted and the immunoreactivity to active caspase-3 and caspase-8 was examined after etanercept administration.
  
  
  RESULTS
  Immunoblot and double immunofluorescence staining revealed suppression of TNF-α, TNFR1, and TNFR2 expression after administration of etanercept in the acute phase of spinal cord injury. LFB staining demonstrated potential myelination in the etanercept-treated group from 2 week after spinal cord injury, together with an increased BBB locomotor score. Double immunofluorescence staining showed a significant decrease in TUNEL-positive neurons and oligodendroglia from 12 hour to 1 week in the gray and white matters after etanercept administration. Immunoblot analysis demonstrated overexpression of activated caspase-3 and caspase-8 after spinal cord injury, which was markedly inhibited by etanercept.
  
  
  CONCLUSIONS
  Our results indicated that etanercept reduces the associated tissue damage of spinal cord injury, improves hindlimb locomotor function, and facilitates myelin regeneration. This positive effect of etanercept on spinal cord injury is probably attributable to the suppression of TNF-α, TNFR1, TNFR2, and activated caspase-3 and caspase-8 overexpressions, and the inhibition of neuronal and oligodendroglial apoptosis.
authors.affiliation: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Japan.
authors.forename: Ke-Bing
authors.initials: KB
authors.lastname: Chen
authors.forename: Kenzo
authors.initials: K
authors.lastname: Uchida
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yayama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hirai
authors.forename: Shuji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Alexander Rodriguez
authors.initials: AR
authors.lastname: Guerrero
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Wei-Ying
authors.initials: WY
authors.lastname: Ma
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Liu
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Baba
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept