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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)\u2010derived BMECs. Our data indicate that all three peptides increase BBB permeability in a concentration\u2010dependent 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\u2010effective concentration also resulted in increased BBB permeability in the iPSC\u2010derived 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\u2010term effects of these peptides are not mediated through alteration of tight\u2010junction proteins claudin\u20105 and occludin, but likely involve redistribution of F\u2010actin 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\u2010documented, direct effect of SP on BBB permeability and adds to the well\u2010recognised actions of BK on BBB. Lastly, we demonstrate that peptidase neurolysin can neutralise the effects of these peptides on BBB, suggesting potential therapeutic implications.<\/jats:p>","DOI":"10.1111\/jne.12931","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T03:57:10Z","timestamp":1611806230000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Neurolysin substrates bradykinin, neurotensin and substance P enhance brain microvascular permeability in a human in vitro model"],"prefix":"10.1111","volume":"33","author":[{"given":"Abraham J.","family":"Al\u2010Ahmad","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences and Center for Blood Brain Barrier Research School of Pharmacy TTUHSC  Amarillo TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iqra","family":"Pervaiz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences 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