Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke. Issue 2 (February 2023)

• Record Type: Journal Article
• Authors: Li, Fengshi; Zhang, Yueman; Li, Ruqi; Li, Yan; Ding, Shenghao; Zhou, Jianpo; Huang, Tianchen; Chen, Chen; Lu, Bingwei; Yu, Weifeng; Boltze, Johannes; Li, Peiying; Wan, Jieqing
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 43:Issue 2(2023)
• Page Start: 241
• Page End: 257
• Publication Date: 2023-02
• Subjects: Ischemic stroke -- Serpina3n -- blood brain barrier (BBB) -- granzyme B -- neutrophil elastase; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X221113897
• Languages: English
• ISSNs: 0271-678X

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.