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.
Intracerebral hemorrhage (ICH), the most devastating and least treatable form of stroke, is induced by a ruptured blood vessel within the brain, leading to neurovascular injury and poor patient outcomes. Our proposed research will demonstrate that remote limb ischemic post-conditioning (RIC) improves neurological outcomes after ICH via a mechanism involving modulation of the immune system. These critical mechanistic studies will provide essential support for the translational of RIC as a safe, non-invasive, and easy-to- administer therapy in ICH patient populations.
|Vaibhav, Kumar; Braun, Molly; Khan, Mohammad Badruzzaman et al. (2018) Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation. J Exp Med 215:2636-2654|
|Braun, Molly; Vaibhav, Kumar; Saad, Nancy et al. (2017) Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury. J Immunol 198:3615-3626|