Abstract T P82: The Role of the A2B Receptor in a Mouse Model Of Stroke
Introduction: Every 40 seconds someone in the United States has a stroke, and we currently spend $73.3 billion on stroke-related disability. A2B receptor agonists are strongly protective against ischemia in many organ systems including liver, lung, and kidney. Very little work has been carried out to uncover the role, if any, for A2B in brain ischemia. The objective of this study was to elucidate the role of the A2B receptor through the use of the middle cerebral artery occlusion mouse model (MCAO), the A2B receptor antagonist PSB1115, and A2B KO animals.
Hypothesis: We hypothesized that the A2B receptor antagonist PSB1115 would be detrimental in stroke.
Methods: Transient focal ischemia was induced for 60 min of middle cerebral artery occlusion (MCAo) using the intraluminal filament model in male C57Bl/6 wild-type and A2B KO mice. PSB1115 at a dose of 5mg/kg and a vehicle of DMSO in saline were blinded and animals were randomized to treatment. Drug was delivered to C57BL/6 mice immediately post-reperfusion in the 60 minute MCAO model. Mice were sacrificed after 24 or 72 hours and infarct volume was measured using 2,3,5-triphenyltetrazolium chloride (TTC). Infarct volumes were compared between drug and vehicle groups and WT and A2B KO mice. Statistical analysis was performed using Student’s t-test with P<0.05 considered significant.
Results: Analysis of histological damage 24 hours after MCAo revealed that the A2B antagonist PSB1115 decreased infarct size from 49±8.0% (n=7) to 37±4.3% (n=10;p<0.005). Similarly, we observed that the same dose of PSB1115 provided prolonged protection (analyzed 72 hours after MCAo), infarct volume decreased from 44±6.4% (n=7) in vehicle treated animals to 22±2.9% (n=4;p<0.05) in PSB115 treated animals. To extend this remarkable observation, we took advantage of A2B KO mice. We observed that A2B KO mice had significantly smaller infarct size at 24h compared to WT littermates, reducing from 55±6.4% (n=4) in WT mice to 19±4.3% (n=6;p<0.05) in A2B KO mice.
Conclusion: Contrary to our hypothesis and its role in other organ systems, blocking or genetic deletion (KO mice) of the A2B receptor conveys protection following experimental stroke.
Author Disclosures: L.B. Weitzel: None. H. Grewal: None. P.S. Herson: None. R.J. Traystman: None.
- © 2015 by American Heart Association, Inc.