Failure of the lipid peroxidation inhibitor, U74006F, to prevent postischemic selective neuronal injury

The lipid peroxidation inhibitor, U74006F, was tested for neuroprotective properties using the rat four-vessel occlusion model. Adult Wistar rats (136) were randomized to receive pretreatment with either vehicle or U74006F, and exposed to either 15 min (n = 103) or 5 min (n = 33) of transient but severe forebrain ischemia. Surviving criterial animals were reperfused for 72 h, and in the multidose experiments, animals were injected with repeated doses of U74006F or vehicle during the reperfusion period. Vehicle-treated animals exposed to 15 min of ischemia sustained 60 +/- 35% (n = 16) CA1 pyramidal cell necrosis whereas U74006F-treated animals lost 61 +/- 30% (3 mg/kg, n = 9), 42 +/- 35% (10 mg/kg, n = 15), 62 +/- 28% (5 x 10 mg/kg, n = 10), and 74 +/- 30% (8 x 10 mg/kg, n = 10) of CA1 pyramidal cells. No improvement was seen in the injury to cortex or striatum with either pre- or pre- and posttreatment with U74006F. For animals suffering 5 min of transient forebrain ischemia, vehicle-treated rats lost 19 +/- 26% (n = 14), whereas U74006F-treated (8 x 10 mg/kg) animals lost 36 +/- 39% (n = 15) of CA1 neurons. In addition, no protection was discerned in the mildly injured striatum or cortex of these animals. Given the potent effect of U74006F in inhibiting iron-dependent lipid peroxidation in vitro, we question the importance of oxy radicals in the mechanism of postischemic selective neuronal injury in vivo.