{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T21:59:20Z","timestamp":1789768760239,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T00:00:00Z","timestamp":1604534400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS085054"],"award-info":[{"award-number":["R01 NS085054"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2021,3]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n A combination of central muscle relaxants, chlorzoxazone and baclofen (chlorzoxazone\u2010baclofen), has been proposed for treatment of cerebellar symptoms in human spinocerebellar ataxia. However, central muscle relaxants can worsen balance. The optimal dose for target engagement without toxicity remains unknown. Using the genetically precise\n Atxn1<\/jats:italic>\n \n 154Q\/2Q<\/jats:italic>\n <\/jats:sup>\n model of spinocerebellar ataxia type 1, we aimed to determine the role of cerebellar dysfunction in motor impairment. We also aimed to identify appropriate concentrations of chlorzoxazone\u2010baclofen needed for target engagement without toxicity to plan for human clinical trials.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We use patch clamp electrophysiology in acute cerebellar slices and immunostaining to identify the specific ion channels targeted by chlorzoxazone\u2010baclofen. Behavioral assays for coordination and grip strength are used to determine specificity of chlorzoxazone\u2010baclofen for improving cerebellar dysfunction without off\u2010target effects in\n Atxn1<\/jats:italic>\n \n 154Q\/2Q<\/jats:italic>\n <\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We identify irregular Purkinje neuron firing in association with reduced expression of ion channels\n Kcnma1<\/jats:italic>\n and\n Cacna1g<\/jats:italic>\n in\n Atxn1<\/jats:italic>\n \n 154Q\/2Q<\/jats:italic>\n <\/jats:sup>\n mice. Using in vitro electrophysiology in brain slices, we identified concentrations of chlorzoxazone\u2010baclofen that improve Purkinje neuron spike regularity without reducing firing frequency. At a disease stage in\n Atxn1<\/jats:italic>\n \n 154Q\/2Q<\/jats:italic>\n <\/jats:sup>\n mice when motor impairment is due to cerebellar dysfunction, orally administered chlorzoxazone\u2010baclofen improves motor performance without affecting muscle strength.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n We identify a tight relationship between baclofen\u2010chlorzoxazone concentrations needed to engage target and levels above which cerebellar function will be compromised. We propose to use this information for a novel clinical trial design, using sequential dose escalation within each subject, to identify dose levels that are likely to improve ataxia symptoms while minimizing toxicity. \u00a9 2020 International Parkinson and Movement Disorder Society<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mds.28355","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T09:14:11Z","timestamp":1604567651000},"page":"622-631","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A Chlorzoxazone\u2010Baclofen Combination Improves Cerebellar Impairment in Spinocerebellar Ataxia Type 1"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3852-127X","authenticated-orcid":false,"given":"David D.","family":"Bushart","sequence":"first","affiliation":[{"name":"Department of Neurology University of Michigan Ann Arbor Michigan USA"},{"name":"Ohio 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