Neurovascular protection by adropin in acute neural injury from subarachnoid hemorrhage

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ABSTRACT Acute neural injury from subarachnoid hemorrhage (SAH)-associated cerebral infarction occurs in 30-40% of patients who survive the initial hemorrhage, leads to death and disability, and most strongly correlates with 3- month outcome. There is also a significant rate of long-term cognitive deficits. Current understanding of the pathophysiology of post-SAH cerebral infarction points to injury cascades involving decreased nitric oxide (NO) bioavailability and oxidative stress. Under normal conditions, NO signaling pathways regulate cerebral blood flow by mediating cerebral vasodilation and inhibiting platelet adhesion. However, with SAH, red blood cells lyse and release hemoglobin, which is a spasmogenic. Hemoglobin scavenges NO; stimulates production of a nitric oxide synthase (NOS) inhibitor (ADMA); and generates reactive oxygen species (ROS) and nitrogen species (RNS). We believe the recently-identified peptide hormone adropin is a promising therapeutic target for post-SAH cerebral infarction. Our group and others have shown adropin is abundantly expressed in the brain, regulates the endothelial nitric oxide synthase (eNOS) pathway, correlates with markers of oxidative stress, and reduces brain endothelial permeability in response to simulated ischemia. Our hypothesis is that adropin confers protection against acute neural injury from post-SAH cerebral infarction. Our overall goal in this proposal is to demonstrate the protective role of adropin in SAH and investigate the underlying molecular and cellular mechanisms of this protection. Our preliminary data support this hypothesis by showing that SAH decreases brain adropin expression, and that endogenous adropin overexpression by transgenic mice with a β-actin-driven adropin transgene (AdrTg) or treatment with synthetic adropin in the SAH model reduces cerebral edema, preserves tight junction protein expression, abolishes microthrombosis, increases eNOS phosphorylation, prevents cerebral vasospasm, and inhibits neuronal apoptosis. Aim 1 is to determine whether adropin confers protection against acute neural injury after SAH when given in a clinically translatable timepoint after SAH. In Aim 2, we will study mediators that regulate Enho gene expression in the setting of SAH. In Aim 3, we will study whether adropin neurovascular protection is mediated via eNOS activity. We expect this study will provide novel knowledge on adropin-mediated protection against acute neural injury after SAH. The significance of this study is that it is directly translatable and the first to investigate the fundamentals of adropin regulation in brain endothelial cells after SAH. This study will provide the preclinical data for a Phase 1/2 human clinical trial in SAH patients.