Abstract WP307: Combinatory Therapy With a PAF-Receptor Antagonist Plus a Lipid Mediator Provides Long-Lasting Protection in Experimental Stroke

Abstract

Objective: Neuroprotective efficacy observed during short survival periods may not necessarily apply to more extended survival periods, and some stroke-impaired behaviors recover naturally in rodent models 1-2 weeks after stroke. The objective of the present study was to test the hypothesis that acute LAU-0901 plus NPD1-induced neuroprotection endures in animals allowed to survive for several weeks after focal ischemic insult. Two small bioactive molecules were investigated: LAU-0901, a PAF-R antagonist that blocks pro-inflammatory signaling, and neuroprotectin D1 (NPD1), which activates cell-survival pathways, and their combination exerts potent anti-inflammatory activity in the brain. Methods: Male SD rats (290-360g) were subjected to 2h of middle cerebral artery occlusion (MCAo) by the intraluminal filament and treated with vehicle, LAU-0901 (60 mg/kg, IP), NPD1 (222 μg/kg, IV), LAU-0901+NPD1 at 3 h after onset of MCAo. Rats received neurobehavioral examinations during MCAo (60 min) and then on days 1, 2, 3, 7, and weekly during eight weeks survival period, followed by ex vivo MRI on weeks 4 and 8. Results: Physiological variables showed no significant differences among groups. No adverse behavioral side effects were observed after administering LAU-0901, NPD1, or LAU-0901+NPD1. LAU-0901 and NPD1 treatments alone significantly improved the behavior compared to the vehicle group on day 1 (by 32 and 33%), day 7 (38 and 40%), week 4 (38 and 39%), and persisting throughout eight weeks of survival period (by 58 and 44%, respectively). Combinatory treatment with LAU-0901+NPD1 dramatically improved behavior on days 1 (by 37), 2 (by 37%), 3 (by 36%), 7 (40%), and on weeks 4 (by 40%), 5 (44%), 6 (44%), 7 (44%) and 8 (41%) compared to vehicle group. Treatments with LAU-0901, NPD1, and NPD1+RvD1 reduced T2WI lesion volumes on week 4 by 32, 41, and 50% and tissue loss on week 8 by 83, 51, and 50%, respectively, compared to vehicles. Conclusion: These data suggest that LAU-0901 and NPD1 alone provide high-grade neuroprotection in the MCAo model. Combinatory therapy with LAU-0901 plus NPD1 is more effective than the single therapy affording synergistic neuroprotection with improved neurological recovery when administered at 3h after focal cerebral ischemia in rats.