{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:59:18Z","timestamp":1790276358111,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,21]],"date-time":"2014-11-21T00:00:00Z","timestamp":1416528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-11-1-0767"],"award-info":[{"award-number":["W81XWH-11-1-0767"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS074886"],"award-info":[{"award-number":["NS074886"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F31-NS080539"],"award-info":[{"award-number":["F31-NS080539"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Farber Family Foundation"},{"name":"Landenberger Foundation"},{"name":"MDA"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Research identified promising therapeutics in cell models of Amyotrophic Lateral Sclerosis (ALS), but there is limited progress translating effective treatments to animal models and patients, and <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> remains a disease with no effective treatment. One explanation stems from an acquired pharmacoresistance driven by the drug efflux transporters P\u2010glycoprotein (P\u2010gp) and breast cancer\u2010resistant protein (<jats:styled-content style=\"fixed-case\">BCRP<\/jats:styled-content>), which we have shown are selectively upregulated at the blood\u2010brain and spinal cord barrier (<jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">BSCB<\/jats:styled-content>) in <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> mice and patients. Pharmacoresistance is well appreciated in other brain diseases, but overlooked in <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> despite many failures in clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we prove that a P\u2010gp\/<jats:styled-content style=\"fixed-case\">BCRP<\/jats:styled-content>\u2010driven pharmacoresistance limits the bioavailability of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> therapeutics using riluzole, the only <jats:styled-content style=\"fixed-case\">FDA<\/jats:styled-content>\u2010approved drug for <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> and a substrate of P\u2010gp and <jats:styled-content style=\"fixed-case\">BCRP<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> mice (<jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>1\u2010G93A) were treated with riluzole and elacridar, to block P\u2010gp and <jats:styled-content style=\"fixed-case\">BCRP<\/jats:styled-content>, and monitored for survival as well as behavioral and physiological parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that riluzole, which normally is not effective when given at onset of symptoms, is now effective in the <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> mice when administered in combination with the P\u2010gp\/<jats:styled-content style=\"fixed-case\">BCRP<\/jats:styled-content> inhibitor elacridar. Chronic elacridar treatment increases riluzole Central nervous system (CNS) penetration, improves behavioral measures, including muscle function, slowing down disease progression, and significantly extending survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our approach improves riluzole efficacy with treatment beginning at symptom onset. Riluzole will not provide a cure, but enhancing its efficacy postsymptoms by addressing pharmacoresistance demonstrates a proof\u2010of\u2010principle concept to consider when developing new <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> therapeutic strategies. We highlight a novel improved therapeutic approach for <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> and demonstrate that pharmacoresistance can no longer be ignored in <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.141","type":"journal-article","created":{"date-parts":[[2014,11,21]],"date-time":"2014-11-21T13:52:39Z","timestamp":1416577959000},"page":"996-1005","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Inhibiting drug efflux transporters improves efficacy of <scp>ALS<\/scp> therapeutics"],"prefix":"10.1002","volume":"1","author":[{"given":"Michael R.","family":"Jablonski","sequence":"first","affiliation":[{"name":"Weinberg Unit for ALS Research Farber Institute for Neuroscience Department of Neuroscience Thomas Jefferson University 900 Walnut Street Philadelphia Pennsylvania 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