Abstract WP274: Novel Platelet-Activating Factor Receptor Antagonists are Highly Neuroprotective in Focal Cerebral Ischemia

Abstract

INTRODUCTION: Platelet-activating factor (PAF) is a bioactive phospholipid that regulates synaptic activity and when overproduced is a potent mediator of leukocyte functions, including platelet aggregation and inflammation. PAF concentration increases during ischemia-reperfusion and is a mediator of neurotoxicity. The inhibition of this process plays a critical role in neuronal survival. We synthesized various analogues and identified them as PAF receptor antagonists, which were then selected for in vivo experiments to evaluate anti-ischemic activity. METHODS: Physiologically controlled Sprague-Dawley rats received 2 h MCAo by poly-L-lysine-coated intraluminal suture. LAU compounds (LAU-0901, LAU-09015, LAU-09018, LAU-09019, LAU-09020 or LAU-09023; 30 mg/kg) or vehicle (45% cyclodextran) was administered IP at 2 h from onset of MCAo. Neurological status was evaluated during occlusion (at 60 min) and on day 1, 2, 3 and 7. Histopathology was carried out on day 7. RESULTS: Physiological variables were stable and showed no significant differences between groups. All LAU compounds significantly reduced the neurobehavioral deficit compared to the vehicle group, beginning from day 1 and persisting through the 7 day survival period. Histologically, the vehicle group showed large hemispheric infarcts with pan-necrosis. By contrast, LAU-treated rats showed preserved hemispheric structure and small subcortical infarcts. Treatment with LAU (LAU-0901, LAU-09015, LAU-09018, LAU-09019, or LAU-09023) significantly reduced total infarct volume compared to the vehicle group by 68%, 52%, 40%, 51% and 54%, respectively. CONCLUSION: Our results clearly indicate that novel LAU PAF receptor antagonists are highly neuroprotective on behavior and reduction of brain infarction in experimental stroke. These compounds may provide the basis for future therapeutics in patients suffering ischemic stroke. This study was supported by NIH, NINDS grant R01 NS046741 (NGB).