Attenuation of postischemic brain hypoperfusion and reperfusion injury by the cyclooxygenase-lipoxygenase inhibitor BW755C.
Arachidonic acid metabolites are believed to be important mediators of tissue injury during reperfusion after cerebral ischemia. To determine whether inhibiting the oxygen-dependent metabolism of arachidonic acid would reduce reperfusion injury, we administered the mixed cyclooxygenase-lipoxygenase inhibitor BW755C (3-amino-1-[m(trifluoromethyl)phenyl]-2-pyrazoline) near the time of reperfusion in a rat model of temporary focal ischemia. The duration of ischemia + reperfusion was 2 hours + 22 hours, 3 hours + 3 hours, or 3 hours + 21 hours. The effects of drug or saline treatment on infarct volume, blood-brain barrier permeability, and blood flow were determined. Cortical blood flow was monitored with laser Doppler flowmetry and blood-brain barrier permeability was evaluated by the Evans blue dye method. Infarct volume was determined in all groups by computerized image analysis of Nissl-stained sections. We found that BW755C treatment significantly attenuated delayed postischemic hypoperfusion in the 3 + 3 group (p < 0.05) and reduced the volume of Evans blue dye staining in the cortex (p < 0.01) and basal ganglia (p < 0.05). Hemispheric swelling was reduced in all treatment groups (p < 0.01), as was total infarct volume in the ischemic hemisphere (p < 0.05). These results support the hypothesis that arachidonic acid metabolites contribute to acute postischemic reperfusion injury and suggest that using a mixed cyclooxygenase-lipoxygenase inhibitor as an adjunct to thrombolytic or revascularization therapy could lengthen the ischemia time after which reperfusion is beneficial.
Chen
J
J
Department of Neurology, School of Medicine, University of California, San Francisco, USA.
Weinstein
P R
PR
Graham
S H
SH
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine