Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

Changjun Yang; Bianca P Lavayen; Lei Liu; Brian D Sanz; Kelly M DeMars; Jonathan Larochelle; Marjory Pompilus; Marcelo Febo; Yu-Yo Sun; Yi-Min Kuo; Mansour Mohamadzadeh; Susan A Farr; Chia-Yi Kuan; Andrew A Butler; Eduardo Candelario-Jalil

doi:10.1016/j.redox.2021.102197

Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

Redox Biol. 2021 Nov 22:48:102197. doi: 10.1016/j.redox.2021.102197. Online ahead of print.

Authors

Affiliations

¹ Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
² Department of Psychiatry, University of Florida, Gainesville, FL, USA.
³ Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA, USA; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁴ Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA, USA; Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan.
⁵ Department of Infectious Diseases & Immunology, University of Florida, Gainesville, FL, USA.
⁶ Department of Internal Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis Veterans Affairs Medical Center, Research Service, John Cochran Division, MO, USA; Department of Pharmacology and Physiology, Saint Louis University, St. Louis, MO, USA; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁷ Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA, USA.
⁸ Department of Pharmacology and Physiology, Saint Louis University, St. Louis, MO, USA; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁹ Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Electronic address: ecandelario@ufl.edu.

Abstract

Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes.

Keywords: Adropin; Blood-brain barrier; Endothelial nitric oxide synthase; Ischemic stroke; Neurobehavioral tests; Neurovascular unit; Permanent middle cerebral artery occlusion.

Abstract

Grants and funding