Platelet-activating factor antagonist BN 50730 attenuates hypoxic-ischemicbrain injury in neonatal rats

Platelet-activating factor (PAF) is a lipid derived from breakdown of cell membranes that is postulated to be a mediator of cerebral ischemic injury. PAF regulates CNS gene transcription via intracellular binding sites. To te st the hypothesis that PAF mediates CNS injury in part by modulating gene t ranscription, we evaluated the neuroprotective effiicacy of the drug BN 507 30, an antagonist of the intracellular (microsomal) CNS PAF binding site, i n the neonatal rat model of unilateral cerebral hypoxia-ischemia. Seven-day -old rats underwent right carotid Ligation followed by a 2.5-h exposure to 8% O-2, and were then treated with BN 50730 (2.5 or 25 mg/kg per dose) or v ehicle, at 0 and 2 h after the end of hypoxia. Ipsilateral cortical, striat al, and hippocampal damage was quantitated either 5 d later, or at 5 wk aft er the insult. Treatment with BN 50730 resulted in approximately 60- 80% re duction in ipsilateral tissue loss at both times. Learning and memory were evaluated 5 wk after insult using the Morris Watermaze place navigation tas k. Severity of cortical and striatal damage correlated significantly with l earning and memory deficits. These results support the hypothesis that PAF is a pathogenetic mediator of hypoxic-ischemic damage in the immature brain . Accumulating evidence suggests that PAF mediates its deleterious effects in the immature CNS via multiple mechanisms.