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Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice

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 signalin...

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Autores principales: Chen, Dongdong, Lee, Jinhwan, Gu, Xiaohuan, Wei, Ling, Yu, Shan Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580122/
https://www.ncbi.nlm.nih.gov/pubmed/26391329
http://dx.doi.org/10.1177/1759091415605114
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author Chen, Dongdong
Lee, Jinhwan
Gu, Xiaohuan
Wei, Ling
Yu, Shan Ping
author_facet Chen, Dongdong
Lee, Jinhwan
Gu, Xiaohuan
Wei, Ling
Yu, Shan Ping
author_sort Chen, Dongdong
collection PubMed
description 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.
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spelling pubmed-45801222015-10-06 Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice Chen, Dongdong Lee, Jinhwan Gu, Xiaohuan Wei, Ling Yu, Shan Ping ASN Neuro Original Article 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. SAGE Publications 2015-09-10 /pmc/articles/PMC4580122/ /pubmed/26391329 http://dx.doi.org/10.1177/1759091415605114 Text en © The Author(s) 2015 http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Article
Chen, Dongdong
Lee, Jinhwan
Gu, Xiaohuan
Wei, Ling
Yu, Shan Ping
Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice
title Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice
title_full Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice
title_fullStr Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice
title_full_unstemmed Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice
title_short Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice
title_sort intranasal delivery of apelin-13 is neuroprotective and promotes angiogenesis after ischemic stroke in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580122/
https://www.ncbi.nlm.nih.gov/pubmed/26391329
http://dx.doi.org/10.1177/1759091415605114
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