title: Early treatment with a novel inhibitor of lipid peroxidation (LY341122) improves histopathological outcome after moderate fluid percussion brain injury in rats.
abstract: OBJECTIVE
  Reactive oxygen species are thought to participate in the pathobiology of traumatic brain injury (TBI). This study determined whether treatment with LY341122, a potent inhibitor of lipid peroxidation and an antioxidant, would provide neuroprotection in a rat model of TBI.
  
  
  METHODS
  To investigate the efficacy of LY341122 in this parasagittal fluid percussion model (1.8-2.1 atm), the rats received oral administration of LY341122 (100 mg/kg) or vehicle 2 hours before and 4 hours after TBI (each group, n = 7). To investigate the therapeutic window for treatment, rats were treated with LY341122 or vehicle for 20 hours by femoral vein infusion starting at 5 minutes, 30 minutes, or 3 hours after TBI (each group, n = 5). Three days after injury, analysis of contusion volumes and the frequency of damaged cortical neurons was conducted.
  
  
  RESULTS
  Oral administration of LY341122 before and after TBI led to a significant reduction in overall contusion volume (3.28 mm3+/-0.75 mm3 [mean +/- standard error of the mean] versus 1.32 mm3 +/- 0.33 mm3; P < 0.05) and also reduced the frequency of damaged cortical neurons (1191.7 +/- 267.1 versus 474.6 +/- 80.2; P < 0.05). In the second experiment, rats treated with LY341122 at 5 minutes or 30 minutes after TBI also demonstrated a significant reduction (P < 0.05) in contusion volume (1.92 mm3 +/- 0.64 mm3 or 1.59 mm3 +/- 0.50 mm3, respectively) compared with vehicle-treated rats (4.32 mm3 +/- 1.15 mm3). A significant reduction in total cortical necrotic neuron counts was also demonstrated in the 5-minute group (2243.8 +/- 265.3 versus 1457.8 +/- 265.3; P < 0.05). In contrast, histopathological outcome was not significantly improved when treatment was delayed until 3 hours after TBI.
  
  
  CONCLUSIONS
  These data reinforce the hypothesis that lipid peroxidation and reactive oxygen species participate in the acute pathogenesis of TBI. Treatment delayed until 3 hours after TBI did not provide significant histopathological protection.
authors.affiliation: Department of Neurology, Neurotrauma Research Center, University of Miami School of Medicine, Florida 33101, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wada
authors.forename: O F
authors.initials: OF
authors.lastname: Alonso
authors.forename: R
authors.initials: R
authors.lastname: Busto
authors.forename: J
authors.initials: J
authors.lastname: Panetta
authors.forename: J A
authors.initials: JA
authors.lastname: Clemens
authors.forename: M D
authors.initials: MD
authors.lastname: Ginsberg
authors.forename: W D
authors.initials: WD
authors.lastname: Dietrich
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D002245:Carbon Dioxide / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D010080:Oxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: C122047:LY 341122; D010080:Oxazoles; D002245:Carbon Dioxide; D010100:Oxygen