Abstract WP211: Mir-34a Modulates Outcomes After Experimental Stroke In Mice

Ischemic stroke is one of the leading causes of death worldwide and causes significant morbidity among survivors. Studies have shown correlations between small noncoding RNAs (microRNAs, miRNAs) and stroke. We have previously reported that miR-34a depletion decreases infarct volume and attenuates neurological deficits in stroke mice. To further investigate the role of miR-34a in stroke, we utilized inducible miR-34a overexpression (miR-34a TG ) mice. Transient middle cerebral artery occlusion (tMCAO) was performed on 6-month old doxycycline-induced miR-34a TG mice compared to wild-type (WT) controls. We confirmed that miR-34a TG mice had a ~5-fold increase of miR-34a in plasma at 24 hours post-stroke as detected by real-time PCR compared with WT naive controls (p < 0.0001) and WT-stroke controls (p < 0.0001). Following ischemia due to 60 min tMCAO, overexpression of miR-34a significantly exacerbated neurological deficit scores (p = 0.0035) and increased infarct volume compared to WT control mice at 24 hours of reperfusion (p = 0.002). Systemic delivery of a locked nucleic acid (LNA)-modified miR-34a inhibitor, antagomir-34a, in stroke mice substantially reduced infarct volume (p = 0.0021) and improved neurological deficits (p = 0.0057) at 24 hours post-stroke. Our post-stroke behavioral study revealed that antagomir-34a significantly improved functional outcomes including motor function assessed by accelerated rotarod tests at 2 weeks post-stroke (p = 0.0046) and memory deficits assessed by Morris Water Maze tests at 4 weeks post-stroke (p = 0.0012). These data demonstrate that miR-34a plays an important role in modulating acute stroke outcomes and suggest that miR-34a may be a promising therapeutic target for stroke therapy.