LAUSR

Introduction: Endothelial dysfunction is an important mediator of post ischemic injury of the heart and brain following ischemia/reperfusion (I/R). We have reported that CD38 activation in heart I/R models leads to NADPH depletion with endothelial nitric oxide synthase (eNOS) impairment, loss of endothelial-mediated coronary dilatation and increased myocardial infarction. While CD38 knockout or inhibition prevents this dysfunction and decreases myocardial infarction, the role of CD38 in ischemic stroke remains uncertain. Hypothesis: We hypothesize that loss of CD38 expression and activity through gene knockout is protective with smaller infarct volume. Methods: 15 week-old male CD38 knock out (KO) n=12 and wild type (WT) mice n=12 underwent middle cerebral artery occlusion (MCAO) for 60 minutes. Stroke volume was calculated using T2 MRI sequences on a 9.4 T MRI system acquired 48 hours post stroke with images analyzed using Osirix software. The ratios of the stroke volume to the affected hemisphere volume and the compensated swelling infarction volume percentage of normal hemisphere were calculated using established methods. Open field test to measure motor impairment was performed at baseline and 48 hours post stroke (KO, n=12, WT n=6). Statistical analysis was completed in STATA using Man-Whitney U test and T-test to compare infarct volumes and cognitive parameters. Values are shown as mean ± SD. P value < 0.05 was considered significant. Results: At 48 hours, brain MRI showed a smaller percentage of cerebral hemisphere affected by stroke in CD38 KO compared to WT (25.9±3.7 vs 41.1±9.4, respectively P=0.0001) and a smaller percentage of compensated swelling infarction volume of normal hemisphere in KO mice compared to WT (19.6±3 vs 33.5±9, respectively P=0.0001). Open field test showed significant post stroke motor impairment in WT compared to CD38KO mice (distance travelled 1.8±1 m vs 4.7±3 m, P=0.04, respectively and average speed 0.006±0.003 m/s vs 0.016±0.01m/s, P=0.04, respectively). Conclusions: Infarct volumes are smaller and motor impairment is decreased in CD38 KO mice compared to WT demonstrating that gene knockout of CD38 confers neuroprotection against acute ischemic brain injury.