title: Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-α.
abstract: BACKGROUND
  Tumor necrosis factor-alpha (TNF-α) is elevated early in injured brain after traumatic brain injury (TBI), in humans and in animals. Etanercept (a TNF-α antagonist with anti-inflammatory effects) attenuates TBI in rats by reducing both microglial and astrocytic activation and increased serum levels of TNF-α. However, it is not known whether etanercept improves outcomes of TBI by attenuating microglia-associated, astrocytes-associated, and/or neurons-associated TNF-α expression in ischemic brain. A well clinically relevant rat model, where a lateral fluid percussion is combined with systemic administration of etanercept immediately after TBI, was used. The neurological severity score and motor function was measured on all rats preinjury and on day 3 after etanercept administration. At the same time, the neuronal and glial production of TNF-α was measured by Immunofluorescence staining. In addition, TNFα contents of ischemic cerebral homogenates was measured using commercial enzyme-linked immunosorbent assay kits.
  
  
  RESULTS
  In addition to inducing brain ischemia as well as neurological and motor deficits, TBI caused significantly higher numbers of microglia-TNF-α double positive cells, but not neurons-TNF-α or astrocytes-TNF-α double positive cells in the injured brain areas than did the sham operated controls, when evaluated 3 days after TBI. The TBI-induced cerebral ischemia, neurological motor deficits, and increased numbers of microglia-TNF-α double positive cells and increased TNF-α levels in the injured brain were all significantly attenuated by etanercept therapy.
  
  
  CONCLUSIONS
  This finding indicates that early microglia overproduction of TNF-α in the injured brain region after TBI contributes to cerebral ischemia and neurological motor deficits, which can be attenuated by etanercept therapy. Studies in this model could provide insight into the mechanisms underlying neurological motor disturbance in brain-injured patients.
authors.affiliation: Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Chung-Ching
authors.initials: CC
authors.lastname: Chio
authors.forename: Chin-Hong
authors.initials: CH
authors.lastname: Chang
authors.forename: Che-Chuan
authors.initials: CC
authors.lastname: Wang
authors.forename: Chong-Un
authors.initials: CU
authors.lastname: Cheong
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Chao
authors.forename: Bor-Chih
authors.initials: BC
authors.lastname: Cheng
authors.forename: Chung-Zhing
authors.initials: CZ
authors.lastname: Yang
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D000068800:Etanercept; D005786:Gene Expression Regulation / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D013778:Tetrazolium Salts; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D007074:Immunoglobulin G; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018124:Receptors, Tumor Necrosis Factor; D013778:Tetrazolium Salts; D014409:Tumor Necrosis Factor-alpha; C009591:triphenyltetrazolium; D000068800:Etanercept