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However, how potential alterations to the blood\u2013brain barrier (BBB) affect the brain exposure of drugs in ALS remains under\u2010investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>\n                      We used high\u2010dimensional proteomic analysis, cellular metabolism, and mitochondrial functional assays to characterise isolated brain microvascular endothelial cells (BMECs) from wildtype and SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      transgenic mice, a mouse model of familial ALS, at a late\u2010symptomatic age (P115\u2013120), together with a transcardiac brain perfusion technique to assess BBB function\n                      <jats:italic>in situ<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>\n                      The BBB of the SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      transgenic (TG) mice was significantly altered, including a 1.3\u2010fold decrease in apparent brain microvascular volume, and decreased BBB transport of\n                      <jats:sup>3<\/jats:sup>\n                      H\u2010diazepam (1.4\u2010fold) and\n                      <jats:sup>3<\/jats:sup>\n                      H\u20102\u2010deoxy\u2010D\u2010glucose (1.2\u2010fold). BMEC proteomic analysis revealed multiple changes in TG mice including altered transmembrane activity, metabolism, and mitochondrial function, as revealed by gene set enrichment analysis, alongside altered glucose transporter (Glut1) abundance. These proteomic findings supported the identified increase in mitochondrial basal\/ATP\u2010linked respiration, mitochondrial action potential, ATP production, and intracellular ATP levels in SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mouse BMECs. The BBB transport of\n                      <jats:sup>3<\/jats:sup>\n                      H\u2010digoxin, a specific ATP\u2010binding cassette efflux P\u2010glycoprotein (P\u2010gp) substrate, was reduced by 11.0% in SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mice. This was confirmed by a 46.7% reduction in BMEC uptake of\n                      <jats:sup>3<\/jats:sup>\n                      H\u2010digoxin, an observation that was reversed by resolving the hypermetabolic state of SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      BMECs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and implications<\/jats:title>\n                    <jats:p>These findings open possible therapeutic avenues that could be exploited to overcome P\u2010gp\u2010mediated CNS drug resistance in ALS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70147","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T05:40:25Z","timestamp":1756791625000},"page":"280-295","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Increased ATP production and P\u2010glycoprotein activity underlie the marked changes in blood\u2013brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1442-3333","authenticated-orcid":false,"given":"Yijun","family":"Pan","sequence":"first","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria Australia"},{"name":"Department of Organ Anatomy Tohoku University Graduate School of Medicine  Sendai Miyagi Japan"},{"name":"Department of Neuroscience, School of Translational Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alanna G.","family":"Spiteri","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health  Parkville Victoria 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