{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:51:19Z","timestamp":1790391079642,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T00:00:00Z","timestamp":1538697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100008994","name":"European Society of Contraception and Reproductive Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008994","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UZH Filling the Gap Program"},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["PMPDP3_145470"],"award-info":[{"award-number":["PMPDP3_145470"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["PP00P3-170683"],"award-info":[{"award-number":["PP00P3-170683"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"P&K P\u00fchringer Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Effective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD\/R) model in primary neuronal cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>MCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD\/R. Desogestrel and drospirenone induced higher expression levels of GABAAR \u03b14 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>For the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke.<\/jats:p><\/jats:sec>","DOI":"10.1093\/cvr\/cvy248","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T20:24:22Z","timestamp":1538684662000},"page":"637-646","source":"Crossref","is-referenced-by-count":18,"title":["Contraceptive drugs mitigate experimental stroke-induced brain injury"],"prefix":"10.1093","volume":"115","author":[{"given":"Mohamad","family":"El Amki","sequence":"first","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Binder","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Steffen","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas R","family":"Luft","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Weller","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Imthurn","sequence":"additional","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele S","family":"Merki-Feld","sequence":"additional","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Wegener","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,10,5]]},"reference":[{"key":"2019090909383581000_cvy248-B1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11886-009-0080-2","article-title":"Stroke in women: disparities and outcomes","volume":"12","author":"Persky","year":"2010","journal-title":"Curr Cardiol Rep"},{"key":"2019090909383581000_cvy248-B2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S1474-4422(11)70269-1","article-title":"An epidemiologic review","volume":"11","author":"Lisabeth","year":"2012","journal-title":"Lancet Neurol"},{"key":"2019090909383581000_cvy248-B3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s11936-009-0025-5","article-title":"Hormone therapy and stroke: is it all about timing?","volume":"11","author":"Bushnell","year":"2009","journal-title":"Curr Treat Options Cardiovasc Med"},{"key":"2019090909383581000_cvy248-B4","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1093\/brain\/awm183","article-title":"Progesterone for the treatment of experimental brain injury; a systematic review","volume":"131","author":"Gibson","year":"2008","journal-title":"Brain"},{"key":"2019090909383581000_cvy248-B5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1515\/hmbci-2013-0048","article-title":"Sex hormones in the cardiovascular system","volume":"18","author":"dos Santos","year":"2014","journal-title":"Horm Mol Biol Clin Investig"},{"key":"2019090909383581000_cvy248-B6","first-page":"1","article-title":"Use of contraception in the United States: 1982-2008","volume":"23","author":"Mosher","year":"2010","journal-title":"Vital Health Stat"},{"key":"2019090909383581000_cvy248-B7","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1093\/humrep\/16.3.469","article-title":"Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol","volume":"16","author":"Roumen","year":"2001","journal-title":"Hum Reprod"},{"key":"2019090909383581000_cvy248-B8","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1186\/s10194-015-0522-8","article-title":"Positive effects of the progestin desogestrel 75 \u03bcg on migraine frequency and use of acute medication are sustained over a treatment period of 180 days","volume":"16","author":"Merki-Feld","year":"2015","journal-title":"J Headache Pain"},{"key":"2019090909383581000_cvy248-B9","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.yhbeh.2012.06.003","article-title":"Progesterone and neuroprotection","volume":"63","author":"Singh","year":"2013","journal-title":"Horm Behav"},{"key":"2019090909383581000_cvy248-B10","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1210\/en.2016-1702","article-title":"Progesterone protects against bisphenol A-induced arrhythmias in female rat cardiac myocytes via rapid signaling","volume":"158","author":"Ma","year":"2017","journal-title":"Endocrinology"},{"key":"2019090909383581000_cvy248-B11","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1093\/brain\/awt319","article-title":"Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study","volume":"137","author":"Wali","year":"2014","journal-title":"Brain"},{"key":"2019090909383581000_cvy248-B12","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.expneurol.2010.08.023","article-title":"Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases","volume":"226","author":"Ishrat","year":"2010","journal-title":"Exp Neurol"},{"key":"2019090909383581000_cvy248-B13","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1210\/en.2012-1138","article-title":"Progesterone receptors: a key for neuroprotection in experimental stroke","volume":"153","author":"Liu","year":"2012","journal-title":"Endocrinology"},{"key":"2019090909383581000_cvy248-B14","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1016\/S0028-3908(99)00233-6","article-title":"GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke","volume":"39","author":"Green","year":"2000","journal-title":"Neuropharmacology"},{"key":"2019090909383581000_cvy248-B15","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1056\/NEJMoa1411090","article-title":"A clinical trial of progesterone for severe traumatic brain injury","volume":"371","author":"Skolnick","year":"2014","journal-title":"N Engl J Med"},{"key":"2019090909383581000_cvy248-B16","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/jcbfm.2012.185","article-title":"Assessing post-stroke behavior in mouse models of focal ischemia","volume":"33","author":"Balkaya","year":"2013","journal-title":"J Cereb Blood Flow Metab"},{"key":"2019090909383581000_cvy248-B17","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.expneurol.2012.08.005","article-title":"Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke","volume":"238","author":"El Amki","year":"2012","journal-title":"Exp Neurol"},{"key":"2019090909383581000_cvy248-B18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jri.2016.12.002","article-title":"Drospirenone reduces inflammatory cytokines, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression in human endometriotic stromal cells","volume":"119","author":"Makabe","year":"2017","journal-title":"J Reprod Immunol"},{"key":"2019090909383581000_cvy248-B19","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1111\/j.1528-1157.1997.tb01197.x","article-title":"Three patterns of catamenial epilepsy","volume":"38","author":"Herzog","year":"1997","journal-title":"Epilepsia"},{"key":"2019090909383581000_cvy248-B20","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1097\/01.WCB.0000125365.83980.00","article-title":"Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice","volume":"24","author":"Gibson","year":"2004","journal-title":"J Cereb Blood Flow Metab"},{"key":"2019090909383581000_cvy248-B21","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1056\/NEJMoa1404304","article-title":"Very early administration of progesterone for acute traumatic brain injury","volume":"371","author":"Wright","year":"2014","journal-title":"N Engl J Med"},{"key":"2019090909383581000_cvy248-B22","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3109\/02699052.2015.1065344","article-title":"Embracing failure: what the phase III progesterone studies can teach about TBI clinical trials","volume":"29","author":"Stein","year":"2015","journal-title":"Brain Inj"},{"key":"2019090909383581000_cvy248-B23","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/j.1365-2265.2007.03046.x","article-title":"Effects of the progestagen-only contraceptive implant implanon on cardiovascular risk factors","volume":"68","author":"Merki-Feld","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2019090909383581000_cvy248-B24","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.contraception.2015.07.014","article-title":"Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability","volume":"92","author":"Archer","year":"2015","journal-title":"Contraception"},{"key":"2019090909383581000_cvy248-B25","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1210\/er.2012-1008","article-title":"Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects","volume":"34","author":"Stanczyk","year":"2013","journal-title":"Endocr Rev"},{"key":"2019090909383581000_cvy248-B26","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1093\/eurheartj\/ehv141","article-title":"Contraception and cardiovascular disease","volume":"36","author":"Roos-Hesselink","year":"2015","journal-title":"Eur Heart J"},{"key":"2019090909383581000_cvy248-B27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3389\/fncir.2013.00135","article-title":"\u03b14\u03b2\u03b4 GABAA receptors and tonic inhibitory current during adolescence: effects on mood and synaptic plasticity","volume":"7","author":"Smith","year":"2013","journal-title":"Front Neural Circuits"},{"key":"2019090909383581000_cvy248-B28","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nature09511","article-title":"Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke","volume":"468","author":"Clarkson","year":"2010","journal-title":"Nature"},{"key":"2019090909383581000_cvy248-B29","article-title":"The flavonoid, 2\u2019-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia","volume":"29","author":"Clarkson","year":"2018","journal-title":"J Cereb Blood Flow Metab"},{"key":"2019090909383581000_cvy248-B30","doi-asserted-by":"crossref","first-page":"44.","DOI":"10.3389\/fendo.2011.00044","article-title":"Neurosteroids and GABA-A receptor function","volume":"2","author":"Wang","year":"2011","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2019090909383581000_cvy248-B31","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/j.1365-2826.2004.01121.x","article-title":"Reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo","volume":"16","author":"Ciriza","year":"2004","journal-title":"J Neuroendocrinol"},{"key":"2019090909383581000_cvy248-B32","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1097\/00002826-199210000-00002","article-title":"GABA-active steroids: endogenous modulators of GABA-gated chloride ion conductance","volume":"15","author":"Deutsch","year":"1992","journal-title":"Clin Neuropharmacol"},{"key":"2019090909383581000_cvy248-B33","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1002\/neu.20327","article-title":"ERK\/MAPK pathway regulates GABAA receptors","volume":"66","author":"Bell-Horner","year":"2006","journal-title":"J Neurobiol"},{"key":"2019090909383581000_cvy248-B34","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neuroscience.2009.06.025","article-title":"Age- and gender-related differences in GABAA receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat","volume":"163","author":"Chudomel","year":"2009","journal-title":"Neuroscience"},{"key":"2019090909383581000_cvy248-B35","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.nbd.2006.11.004","article-title":"Gender and age differences in expression of GABAA receptor subunits in rat somatosensory thalamus and cortex in an absence epilepsy model","volume":"25","author":"Li","year":"2007","journal-title":"Neurobiol Dis"},{"key":"2019090909383581000_cvy248-B36","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/BF00964918","article-title":"Changes with aging in the levels of amino acids in rat CNS structural elements. I. Glutamate and related amino acids","volume":"14","author":"Banay-Schwartz","year":"1989","journal-title":"Neurochem Res"},{"key":"2019090909383581000_cvy248-B37","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1093\/cercor\/bhh191","article-title":"Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex","volume":"15","author":"Ling","year":"2005","journal-title":"Cereb Cortex"},{"key":"2019090909383581000_cvy248-B38","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S0378-5955(01)00294-5","article-title":"Age-related temporal processing speed deterioration in auditory cortex","volume":"158","author":"Mendelson","year":"2001","journal-title":"Hear Res"},{"key":"2019090909383581000_cvy248-B39","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S0014-4886(03)00121-3","article-title":"Long-term effects of clomethiazole in a model of global ischemia","volume":"182","author":"Chaulk","year":"2003","journal-title":"Exp Neurol"},{"key":"2019090909383581000_cvy248-B40","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.3171\/2012.11.JNS12408","article-title":"The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success","volume":"118","author":"Turner","year":"2013","journal-title":"J Neurosurg"},{"key":"2019090909383581000_cvy248-B41","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1002\/jnr.21370","article-title":"Progesterone increases brain-derived neuroptrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants","volume":"85","author":"Kaur","year":"2007","journal-title":"J Neurosci Res"},{"key":"2019090909383581000_cvy248-B42","doi-asserted-by":"crossref","first-page":"1.","DOI":"10.1155\/2014\/723060","article-title":"Perspectives on molecular biomarkers of oxidative stress and antioxidant strategies in traumatic brain injury","volume":"2014","author":"Mendes Arent","year":"2014","journal-title":"Biomed Res Int"},{"key":"2019090909383581000_cvy248-B43","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.brainres.2009.01.045","article-title":"Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone","volume":"1263","author":"Sayeed","year":"2009","journal-title":"Brain Res"},{"key":"2019090909383581000_cvy248-B44","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.expneurol.2005.09.014","article-title":"Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats","volume":"197","author":"Robertson","year":"2006","journal-title":"Exp Neurol"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cardiovascres\/article-pdf\/115\/3\/637\/29816236\/cvy248.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T01:24:37Z","timestamp":1720661077000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/115\/3\/637\/5115997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,5]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,10,5]]},"published-print":{"date-parts":[[2019,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvy248","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,3,1]]},"published":{"date-parts":[[2018,10,5]]}}}