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M\u00f8ller og Hustru Chastine Mc-Kinney M\u00f8llers Fond til almene Formaal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005747","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009997","name":"International Headache Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["276\u20102018\u2010403"],"award-info":[{"award-number":["276\u20102018\u2010403"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["380\u20102021\u20101140"],"award-info":[{"award-number":["380\u20102021\u20101140"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Female rats were implanted with telemetric ICP probes for physiological, freely moving 24\/7 ICP recordings. Randomised cross\u2010over studies were performed, where rats received acute (24\u2009h) high doses of acetazolamide and topiramate, and chronic (10\u00a0days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT\u2010qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120\u2009min of administration, and in combination doubled the ICP reduction over a 24\u2010h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of <jats:italic>Slc12a2<\/jats:italic> and <jats:italic>Slc4a10<\/jats:italic> and protein expression of the sodium\u2010dependent chloride\/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16213","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T05:26:25Z","timestamp":1691558785000},"page":"70-86","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Acetazolamide and topiramate lower intracranial pressure through differential mechanisms: The effect of acute and chronic administration"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5066-8306","authenticated-orcid":false,"given":"Connar Stanley James","family":"Westgate","sequence":"first","affiliation":[{"name":"Danish Headache Center, Department of Neurology, Glostrup Research Institute, Rigshospitalet\u2010Glostrup University of Copenhagen  Copenhagen 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