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Early treatment with a novel inhibitor of lipid peroxidation (LY341122) improves histopathological outcome after moderate fluid percussion brain injury in rats.

AbstractOBJECTIVE:
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.
CONCLUSION:
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.
AuthorsK Wada, O F Alonso, R Busto, J Panetta, J A Clemens, M D Ginsberg, W D Dietrich
JournalNeurosurgery (Neurosurgery) Vol. 45 Issue 3 Pg. 601-8 (Sep 1999) ISSN: 0148-396X [Print] United States
PMID10493379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • LY 341122
  • Oxazoles
  • Carbon Dioxide
  • Oxygen
Topics
  • Administration, Oral
  • Animals
  • Blood Pressure (drug effects)
  • Brain (drug effects, pathology)
  • Brain Injuries (drug therapy, pathology, physiopathology)
  • Carbon Dioxide (blood)
  • Lipid Peroxidation (drug effects)
  • Male
  • Oxazoles (administration & dosage, therapeutic use)
  • Oxygen (blood)
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

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