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- W3121900526 abstract "Increased brain microvascular permeability and disruption of blood-brain barrier (BBB) function are among hallmarks of several acute neurodegenerative disorders, including stroke. Numerous studies suggest the involvement of bradykinin (BK), neurotensin (NT) and substance P (SP) in BBB impairment and oedema formation after stroke; however, there is paucity of data in regard to the direct effects of these peptides on the brain microvascular endothelial cells (BMECs) and BBB. The present study aimed to evaluate the direct effects of BK, NT and SP on the permeability of BBB in an in vitro model based on human induced pluripotent stem cell (iPSC)-derived BMECs. Our data indicate that all three peptides increase BBB permeability in a concentration-dependent manner in an in vitro model formed from two different iPSC lines (CTR90F and CTR65M) and widely used hCMEC/D3 human BMECs. The combination of BK, NT and SP at a sub-effective concentration also resulted in increased BBB permeability in the iPSC-derived model indicating potentiation of their action. Furthermore, we observed abrogation of BK, NT and SP effects with pretreatment of pharmacological blockers targeting their specific receptors. Additional mechanistic studies indicate that the short-term effects of these peptides are not mediated through alteration of tight-junction proteins claudin-5 and occludin, but likely involve redistribution of F-actin and secretion of vascular endothelial growth factor. This is the first experimental study to document the increased permeability of the BBB in response to direct action of NT in an in vitro model. In addition, our study confirms the expected but not well-documented, direct effect of SP on BBB permeability and adds to the well-recognised actions of BK on BBB. Lastly, we demonstrate that peptidase neurolysin can neutralise the effects of these peptides on BBB, suggesting potential therapeutic implications." @default.
- W3121900526 created "2021-02-01" @default.
- W3121900526 creator A5012911330 @default.
- W3121900526 creator A5037761449 @default.
- W3121900526 creator A5057900193 @default.
- W3121900526 date "2021-01-28" @default.
- W3121900526 modified "2023-10-16" @default.
- W3121900526 title "Neurolysin substrates bradykinin, neurotensin and substance P enhance brain microvascular permeability in a human in vitro model" @default.
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- W3121900526 doi "https://doi.org/10.1111/jne.12931" @default.
- W3121900526 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8166215" @default.
- W3121900526 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33506602" @default.
- W3121900526 hasPublicationYear "2021" @default.
- W3121900526 type Work @default.
- W3121900526 sameAs 3121900526 @default.