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Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke
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Li, Fengshi, Zhang, Yueman, Li, Ruqi, Li, Yan, Ding, Shenghao, Zhou, Jianpo, Huang, Tianchen, Chen, Chen, Lu, Bingwei, Yu, Weifeng, Boltze, Johannes, Li, Peiying and Wan, Jieqing (2022) Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke. Journal of Cerebral Blood Flow & Metabolism . (In Press)
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Abstract
Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1-/- mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Cerebral ischemia, Cerebral ischemia -- Treatment , Blood-brain barrier, Serine proteinases -- Inhibitors, Leucocyte elastase | ||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Journal of Cerebral Blood Flow & Metabolism | ||||||||||||||||||||||||||||||||||||||||||
| Publisher: | Sage Publications Ltd. | ||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 0271-678X | ||||||||||||||||||||||||||||||||||||||||||
| Official Date: | 2022 | ||||||||||||||||||||||||||||||||||||||||||
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| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||||||||||||||
| Publication Status: | In Press | ||||||||||||||||||||||||||||||||||||||||||
| Reuse Statement (publisher, data, author rights): | Posted ahead of print. Li, Fengshi, Zhang, Yueman, Li, Ruqi, Li, Yan, Ding, Shenghao, Zhou, Jianpo, Huang, Tianchen, Chen, Chen, Lu, Bingwei, Yu, Weifeng, Boltze, Johannes, Li, Peiying and Wan, Jieqing (2022) Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke. Journal of Cerebral Blood Flow & Metabolism. Copyright © 2022 (Copyright Holder). Reprinted by permission of SAGE Publications. DOI: [DOI] Users who receive access to an article through a repository are reminded that the article is protected by copyright and reuse is restricted to non-commercial and no derivative uses. | ||||||||||||||||||||||||||||||||||||||||||
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