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Aim: The purpose of the present study was to analyse the impact of a broad selection of high potency MEK1\/2 inhibitors in an organ culture model and use the IC50 values obtained from the organ culture to select highly potent inhibitors for pre-clinical in vivo studies. Results: Nine highly potent mitogen activated protein kinase kinase (MEK1\/2) inhibitors were screened and the two most potent inhibitors from the organ culture screening, trametinib and PD0325901, were tested in an in vivo experimental rat SAH model with intrathecal injections. Subsequently, the successful inhibitor trametinib was administered intraperitoneally in a second in vivo study. In both regimens, trametinib treatment caused significant reductions in the endothelin-1 induced contractility after SAH, which is believed to be associated with endothelin B receptor up-regulation. Trametinib treated rats showed improved neurological scores, evaluated by the ability to traverse a rotating pole, after induced SAH. Conclusion: The PD0325901 treatment did not improve the neurological score after SAH, nor showed any beneficial therapeutic effect on the contractility, contrasting with the reduction in neurological deficits seen after trametinib treatment. These data show that trametinib might be a potential candidate for treatment of SAH.<\/jats:p>","DOI":"10.1042\/cs20190636","type":"journal-article","created":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T16:15:23Z","timestamp":1565108123000},"page":"1797-1811","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Pre-clinical effects of highly potent MEK1\/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage"],"prefix":"10.1042","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5754-1068","authenticated-orcid":false,"given":"Simon T.","family":"Christensen","sequence":"first","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian A.","family":"Haanes","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stine","family":"Spray","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sofie","family":"Grell","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Warfvinge","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"},{"name":"Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Edvinsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"},{"name":"Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Johansson","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2019,8,20]]},"reference":[{"key":"2021113012314497000_B1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrneurol.2013.246","article-title":"Delayed neurological deterioration after subarachnoid haemorrhage","volume":"10","author":"Macdonald","year":"2014","journal-title":"Nat. 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