U78517F is a novel inhibitor of
iron-catalyzed lipid peroxidation that combines the tetramethylchroman
antioxidant ring portion of
alpha-tocopherol with the
amine of the previously described 21-aminosteroids (e.g.,
U74006F).
U78517F inhibited 200 microM FeCl2-initiated lipid peroxidation in rat brain homogenates by 50% at a concentration of 0.6 microM compared with 8 microM for
U74006F, 28 microM for
alpha-tocopherol, and 43 microM for the ring portion of
alpha-tocopherol (i.e.,
trolox).
U78517F is devoid of hypothermic or antiexcitotoxic actions or interactions with known
neurotransmitter receptors. When administered intraperitoneally to male gerbils
at 10 minutes before and again at the end of a 3-hour period of unilateral carotid artery occlusion,
U78517F decreased 24-hour postischemic cortical neuronal
necrosis. Neuronal density in the medial portion of the cortex was increased from 34.2% of normal in vehicle-treated animals to 86.3% in the U78517F-treated animals. In the lateral cortical area, the vehicle group showed only 3.3% neuronal survival versus 48.2% in the
drug-treated group. In a separate series of experiments with the same focal
ischemia model, identical dosing with
U78517F enhanced the postischemic recovery of cortical extracellular
calcium without any effect on ischemic or postischemic cortical blood flow. The effect on
calcium recovery was observed at intraperitoneal doses as low as 0.1 mg/kg. The compound also was effective in partially attenuating 1-week postischemic hippocampal CA1 neuronal loss in a gerbil global
ischemia model involving brief (15-minute) bilateral carotid occlusion, but sustained dosing was required. These results document the anti-ischemic efficacy of a novel and potent inhibitor of
iron-catalyzed lipid peroxidation and further support a key role of
oxygen radicals in postischemic brain damage.