Immune Mechanisms of Protection by Remote Limb Ischemic Conditioning after Intracerebral Hemorrhage

? DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes, with 67,000 Americans suffering an ICH annually. ICH induces the highest acute mortality and the worst long-term neurological outcomes of all types of stroke. ICH is caused by a ruptured blood vessel within the brain, leading to the formation of a space occupying hematoma. Hematoma volume is clinically associated with neurological deterioration and higher mortality, yet a critical barrier to improvin patient outcomes remains a lack of efficacious therapeutic options. Recent work by our laboratory showed remote limb ischemic post- conditioning (RIC) increases cerebral blood flow and improves outcomes after focal cerebral ischemia. Additionally, our pilot data herein showed that RIC reduces neurovascular injury after experimental ICH. Herein, we test the overarching hypothesis that RIC reduces neurological injury after ICH via AMPK-dependent regulation of macrophage polarization. Specific Aim 1 will test the hypothesis that RIC promotes M2 macrophage polarization after ICH via activation of myeloid AMPK. Specific Aim 2 will test the hypothesis that RIC promotes neurological recovery after ICH via activation of myeloid AMPK. Together, these studies will show that RIC provides a non-invasive, clinically feasible, immune mechanism of neurological recovery after ICH. We will also demonstrate that activation of myeloid AMPK reduces long-term injury after ICH.