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Despite its high efficacy and barrier to resistance, ART\u2010associated neuropsychiatric adverse effects remain a major concern. Recent studies have identified a potential interaction between the INSTI, dolutegravir (DTG), and folate transport pathways at the placental barrier. We hypothesized that such interactions could also occur at the two major blood\u2013brain interfaces: blood\u2010cerebrospinal fluid barrier (BCSFB) and blood\u2013brain barrier (BBB). To address this question, we evaluated the effect of two INSTIs, DTG and bictegravir (BTG), on folate transporters and receptor expression at the mouse BCSFB and the BBB in\u00a0vitro, ex\u00a0vivo and in\u00a0vivo. We demonstrated that DTG but not BTG significantly downregulated the mRNA and\/or protein expression of folate transporters (RFC\/\n                    <jats:italic>SLC19A1<\/jats:italic>\n                    , PCFT\/\n                    <jats:italic>SLC46A1<\/jats:italic>\n                    ) in human and mouse BBB models in\u00a0vitro, and mouse brain capillaries ex\u00a0vivo. Our in\u00a0vivo study further revealed a significant downregulation in\n                    <jats:italic>Slc19a1<\/jats:italic>\n                    and\n                    <jats:italic>Slc46a1<\/jats:italic>\n                    mRNA expression at the BCSFB and the BBB following a 14\u2010day DTG oral treatment in C57BL\/6 mice. However, despite the observed downregulatory effect of DTG in folate transporters\/receptor at both brain barriers, a 14\u2010day oral treatment of DTG\u2010based ART did not significantly alter the brain folate level in animals. Interestingly, DTG treatment robustly elevated the mRNA and\/or protein expression of pro\u2010inflammatory cytokines and chemokines (\n                    <jats:italic>Cxcl1, Cxcl2, Cxcl3, Il6, Il23, Il12<\/jats:italic>\n                    ) in primary cultures of mouse brain microvascular endothelial cells (BBB). DTG oral treatment also significantly upregulated proinflammatory cytokines and chemokine (\n                    <jats:italic>Il6, Il1\u03b2, Tnf\u03b1, Ccl2<\/jats:italic>\n                    ) at the BCSFB in mice. We additionally observed a downregulated mRNA expression of drug efflux transporters (\n                    <jats:italic>Abcc1, Abcc4<\/jats:italic>\n                    , and\n                    <jats:italic>Abcb1a<\/jats:italic>\n                    ) and tight junction protein (\n                    <jats:italic>Cldn3<\/jats:italic>\n                    ) at the CP isolated from mice treated with DTG. Despite the structural similarities, BTG only elicited minor effects on the markers of interest at both the BBB and BCSFB. In summary, our current data demonstrates that DTG but not BTG strongly induced inflammatory responses in a rodent BBB and BCSFB model. Together, these data provide valuable insights into the mechanism of DTG\u2010induced brain toxicity, which may contribute to the pathogenesis of DTG\u2010associated neuropsychiatric adverse effect.\n                  <\/jats:p>","DOI":"10.1096\/fj.202400558r","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T01:06:37Z","timestamp":1720573597000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antiretroviral drug dolutegravir induces inflammation at the mouse brain barriers"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6622-8959","authenticated-orcid":false,"given":"Chang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4802-0257","authenticated-orcid":false,"given":"Md. 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