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Its potential benefits in ischemic stroke have not been investigated sufficiently. Mice were subjected to 2\u2009hours of transient middle cerebral artery occlusion (MCAO). Mice were orally treated with ticagrelor (10 or 30\u2009mg\/kg), aspirin (60\u2009mg\/kg), or vehicle at 3 and 24\u2009hours before MCAO and 0 and 6\u2009hours after reperfusion. The infarct volume and neurological deficits 22\u2009hours after reperfusion were evaluated. Cerebral blood flow (CBF) within 24\u2009hours after MCAO was monitored. We performed western blotting and <jats:italic>in vitro<\/jats:italic> analysis using oxygen-glucose deprivation (OGD) stress in human brain microvessel endothelial cells (HBMVECs) to investigate the protective effects of ticagrelor. Ticagrelor (30\u2009mg\/kg) improved neurological deficits, reduced the infarct volume, and improved CBF. It promoted the phosphorylation of endothelial nitric oxide synthase (eNOS) and extracellular signal-regulated kinase 1\/2 (ERK1\/2) during the early phase after reperfusion. Increased phosphorylation of eNOS and ERK1\/2 were also observed in HBMVECs after OGD stress. Ticagrelor attenuate ischemia reperfusion injury possibly via phosphorylation of eNOS and ERK1\/2 in endothelial cells. This suggests that ticagrelor has neuroprotective effects via mechanisms other than its antiplatelet action.<\/jats:p>","DOI":"10.1038\/s41598-017-12205-w","type":"journal-article","created":{"date-parts":[[2017,9,15]],"date-time":"2017-09-15T11:18:58Z","timestamp":1505474338000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Effects of ticagrelor in a mouse model of ischemic stroke"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5592-4188","authenticated-orcid":false,"given":"Keita","family":"Yamauchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiko","family":"Imai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamitsu","family":"Shimazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Iwama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,21]]},"reference":[{"key":"12205_CR1","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1016\/S0140-6736(08)60694-7","volume":"371","author":"GA Donnan","year":"2008","unstructured":"Donnan, G. A., Fisher, M., Macleod, M. & Davis, S. M. Stroke. Lancet \n                           371, 1612\u20131623, https:\/\/doi.org\/10.1016\/S0140-6736(08)60694-7 (2008).","journal-title":"Lancet"},{"key":"12205_CR2","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1056\/NEJMoa0904327","volume":"361","author":"L Wallentin","year":"2009","unstructured":"Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England journal of medicine \n                           361, 1045\u20131057, https:\/\/doi.org\/10.1056\/NEJMoa0904327 (2009).","journal-title":"The New England journal of medicine"},{"key":"12205_CR3","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.jacc.2010.11.016","volume":"57","author":"DJ Schneider","year":"2011","unstructured":"Schneider, D. J. Mechanisms potentially contributing to the reduction in mortality associated with ticagrelor therapy. Journal of the American College of Cardiology \n                           57, 685\u2013687, https:\/\/doi.org\/10.1016\/j.jacc.2010.11.016 (2011).","journal-title":"Journal of the American College of Cardiology"},{"key":"12205_CR4","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1177\/1074248413511693","volume":"19","author":"D Armstrong","year":"2014","unstructured":"Armstrong, D. et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. Journal of cardiovascular pharmacology and therapeutics \n                           19, 209\u2013219, https:\/\/doi.org\/10.1177\/1074248413511693 (2014).","journal-title":"Journal of cardiovascular pharmacology and therapeutics"},{"key":"12205_CR5","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1161\/ATVBAHA.114.304002","volume":"34","author":"MK Nanhwan","year":"2014","unstructured":"Nanhwan, M. K. et al. Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arteriosclerosis, thrombosis, and vascular biology \n                           34, 2078\u20132085, https:\/\/doi.org\/10.1161\/ATVBAHA.114.304002 (2014).","journal-title":"Arteriosclerosis, thrombosis, and vascular biology"},{"key":"12205_CR6","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1056\/NEJMoa1603060","volume":"375","author":"SC Johnston","year":"2016","unstructured":"Johnston, S. C. et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. The New England journal of medicine \n                           375, 35\u201343, https:\/\/doi.org\/10.1056\/NEJMoa1603060 (2016).","journal-title":"The New England journal of medicine"},{"key":"12205_CR7","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/jcbfm.2014.45","volume":"34","author":"P Gelosa","year":"2014","unstructured":"Gelosa, P. et al. Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism \n                           34, 979\u2013988, https:\/\/doi.org\/10.1038\/jcbfm.2014.45 (2014).","journal-title":"Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism"},{"key":"12205_CR8","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1111\/bph.12108","volume":"169","author":"A Sugidachi","year":"2013","unstructured":"Sugidachi, A. et al. A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats. 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