{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:39:06Z","timestamp":1780533546468,"version":"3.54.1"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T00:00:00Z","timestamp":1649462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001779","name":"Monash University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001779","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>P\u2010glycoprotein (P\u2010gp) is an efflux transporter at the blood\u2013brain barrier (BBB) that hinders brain access of substrate drugs and clears endogenous molecules such as amyloid beta (A\u03b2) from the brain. As biometals such as copper (Cu) modulate many neuronal signalling pathways linked to P\u2010gp regulation, it was hypothesised that the bis(thiosemicarbazone) (BTSC) Cu\u2010releasing complex, copper II glyoxal bis(4\u2010methyl\u20103\u2010thiosemicarbazone) (Cu<jats:sup>II<\/jats:sup>[GTSM]), would enhance P\u2010gp expression and function at the BBB, while copper II diacetyl bis(4\u2010methyl\u20103\u2010thiosemicarbazone) (Cu<jats:sup>II<\/jats:sup>[ATSM]), which only releases Cu under hypoxic conditions, would not modulate P\u2010gp expression. Following treatment with 25\u2013250\u2009nM Cu<jats:sup>II<\/jats:sup>(BTSC)s for 8\u201348\u2009h, expression of P\u2010gp mRNA and protein in human brain endothelial (hCMEC\/D3) cells was assessed by RT\u2010qPCR and Western blot, respectively. P\u2010gp function was assessed by measuring accumulation of the fluorescent P\u2010gp substrate, rhodamine 123 and intracellular Cu levels were quantified by inductively coupled plasma mass spectrometry. Interestingly, Cu<jats:sup>II<\/jats:sup>(ATSM) significantly enhanced P\u2010gp expression and function 2\u2010fold and 1.3\u2010fold, respectively, whereas Cu<jats:sup>II<\/jats:sup>(GTSM) reduced P\u2010gp expression 0.5\u2010fold and function by 200%. As both compounds increased intracellular Cu levels, the effect of different BTSC backbones, independent of Cu, on P\u2010gp expression was assessed. However, only the Cu\u2010ATSM complex enhanced P\u2010gp expression and this was mediated partly through activation (1.4\u2010fold) of the extracellular signal\u2010regulated kinase 1 and 2, an outcome that was significantly attenuated in the presence of an inhibitor of the mitogen\u2010activated protein kinase regulatory pathway. Our findings suggest that Cu<jats:sup>II<\/jats:sup>(ATSM) and Cu<jats:sup>II<\/jats:sup>(GTSM) have the potential to modulate the expression and function of P\u2010gp at the BBB to impact brain drug delivery and clearance of A\u03b2.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15609-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15609","type":"journal-article","created":{"date-parts":[[2022,3,19]],"date-time":"2022-03-19T01:53:40Z","timestamp":1647654820000},"page":"226-244","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Copper bis(thiosemicarbazone) complexes modulate P\u2010glycoprotein expression and function in human brain microvascular endothelial cells"],"prefix":"10.1111","volume":"162","author":[{"given":"Jae","family":"Pyun","sequence":"first","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan E.","family":"McInnes","sequence":"additional","affiliation":[{"name":"Bio21 Molecular Science and Biotechnology Institute University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Donnelly","sequence":"additional","affiliation":[{"name":"Bio21 Molecular Science and Biotechnology Institute University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Mawal","sequence":"additional","affiliation":[{"name":"Oxidation Biology Lab, Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental 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