{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:16:17Z","timestamp":1791350177094,"version":"4.3.1"},"reference-count":66,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,8,7]],"date-time":"2020-08-07T00:00:00Z","timestamp":1596758400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009997","name":"International Headache Society","doi-asserted-by":"publisher","award":["2017"],"award-info":[{"award-number":["2017"]}],"id":[{"id":"10.13039\/100009997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001722","name":"Koninklijke Nederlandse Akademie van Wetenschappen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001722","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000654","name":"Marie Curie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000654","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Calcitonin gene\u2013related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP\u2010mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Middle cerebral artery was occluded for 12 to 60\u2009minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1\u20131mg\/kg) or rimegepant (single doses of 10\u2013100mg\/kg) versus vehicle. We also determined their potency on CGRP\u2010induced relaxations in mouse and human vessels, in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Olcegepant (1mg\/kg, single dose) increased infarct risk after 12\u2010 to 20\u2010minute occlusions mimicking transient ischemic attacks (14\/19 vs 6\/18 with vehicle, relative risk\u2009=\u20092.21, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.022), and doubled infarct volumes (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and worsened neurological deficits (median score\u2009=\u20099 vs 5 with vehicle, <jats:italic>p<\/jats:italic>\u2009=\u20090.008) after 60\u2010minute occlusion. Ten daily doses of 0.1 to 1mg\/kg olcegepant yielded similar results. Rimegepant 10mg\/kg increased infarct volumes by 60% after 20\u2010minute ischemia (<jats:italic>p<\/jats:italic>\u2009=\u20090.03); 100mg\/kg caused 75% mortality after 60\u2010minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg\/kg increased infarct size after 30\u2010minute occlusion (1.6\u2010fold, <jats:italic>p<\/jats:italic>\u2009=\u20090.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10\u2010fold more potent than rimegepant on CGRP\u2010induced relaxations in mouse aorta.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. <jats:bold>ANN NEUROL 2020;88:771\u2013784<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25831","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T09:42:32Z","timestamp":1593078152000},"page":"771-784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":113,"title":["Anti\u2010migraine Calcitonin Gene\u2013Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice"],"prefix":"10.1002","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6609-2206","authenticated-orcid":false,"given":"Inge A.","family":"Mulder","sequence":"first","affiliation":[{"name":"Department of Radiology Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiology Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"de Vries","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Vascular Medicine, Department of Internal Medicine Erasmus University Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Radiology Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"Department of Radiology Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7666-2620","authenticated-orcid":false,"given":"Kazutaka","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Department of Radiology Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoon","family":"van den Bogaerdt","sequence":"additional","affiliation":[{"name":"ETB\u2010BISLIFE, Heart Valve Bank  Beverwijk the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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