title: Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice.
abstract: Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV + /5-bromo-2'-deoxyuridin + colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13.
authors.affiliation: Deptartment of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affair Medical Center, Decatur, GA, USA.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Deptartment of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affair Medical Center, Decatur, GA, USA.
authors.forename: Jinhwan
authors.initials: J
authors.lastname: Lee
authors.affiliation: Deptartment of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affair Medical Center, Decatur, GA, USA.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Gu
authors.affiliation: Deptartment of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affair Medical Center, Decatur, GA, USA Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.affiliation: Deptartment of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affair Medical Center, Decatur, GA, USA spyu@emory.edu.
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
mesh_terms: D000281:Administration, Intranasal; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D008297:Male; D008810:Mice, Inbred C57BL; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D043925:Angiogenesis Inducing Agents; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; C495199:apelin-13 peptide
keywords: angiogenesis; apelin-13; functional recovery; inflammation; ischemic stroke; neuroprotection