Abstract WP315: Neuroprotective Effects of Endogenous Adropin in Experimental Ischemic Stroke

Abstract

Adropin is an endogenous peptide highly expressed in the brain and is encoded by the energy homeostasis-associated gene, Enho . We recently found that treatment with synthetic adropin peptide reduces infarct volume in ischemic stroke. This protection by exogenous adropin is associated with a significant increase in endothelial nitric oxide synthase (eNOS) phosphorylation (Ser 1176 ) and reduction of blood-brain barrier (BBB) permeability. However, it is not known whether endogenous adropin modulates ischemic brain damage. We hypothesize that lack of brain adropin increases stroke damage by exacerbating neurovascular dysfunction, while overexpression of this peptide decreases ischemic brain injury. We measured infarct size and BBB damage in male and female adropin overexpressing transgenics (AdrTg), adropin knockout ( Enho -/- ), and corresponding wild-type (WT) control mice subjected to permanent middle cerebral artery occlusion (pMCAO). At 48h after stroke, infarct volume was significantly smaller in AdrTg mice of both sexes compared to WT controls, while stroke resulted in a much larger infarction in both male and female Enho -/- compared to Enho +/+ mice. Brain levels of IgG and albumin, two sensitive markers of BBB disruption, were significantly reduced in AdrTg mice compared to the WT group, while the levels of these two plasma proteins in the ischemic brain of Enho -/- mice were dramatically increased compared to Enho +/+ animals after stroke. Latex vessel casting showed no differences in cerebrovascular anatomy or the diameter of the main brain arteries between Enho -/- , AdrTg and their respective WT controls. In AdrTg mice, we found a positive correlation between brain adropin levels and eNOS phosphorylation. These data suggest that increased eNOS phosphorylation by adropin is a potential mechanism underlying its protective effects in stroke. Consistent with this hypothesis, the protective effects of adropin were completely abolished in eNOS knockout (eNOS -/- ) mice subjected to pMCAO. Taken together, our findings show for the first time that endogenous adropin is a neuroprotective peptide in ischemic stroke. Understanding adropin signaling and function could offer a novel therapeutic strategy for the treatment of ischemic brain damage.