{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:10:08Z","timestamp":1785514208964,"version":"3.56.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney. Here, we examine the mechanism of action of meclizine and report the efficacy and improved safety of the\n              <jats:italic toggle=\"yes\">(S<\/jats:italic>\n              ) enantiomer.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We determined the anoxic depolarization latency, tissue and neurological outcomes, and glucose uptake using micro\u2013positron emission tomography after transient middle cerebral artery occlusion in mice pretreated (\u221217 and \u22123 hours) with either vehicle or meclizine. To exclude a direct effect on tissue excitability, we also examined spreading depression susceptibility. Furthermore, we accomplished the chiral synthesis of\n              <jats:italic toggle=\"yes\">(R<\/jats:italic>\n              )- and\n              <jats:italic toggle=\"yes\">(S<\/jats:italic>\n              )-meclizine and compared their effects on oxygen consumption and histamine H1 receptor binding along with their brain concentrations.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Micro\u2013positron emission tomography showed meclizine increases glucose uptake in the ischemic penumbra, providing the first in vivo evidence that the neuroprotective effect of meclizine indeed stems from its ability to toggle metabolism toward glycolysis. Consistent with reduced reliance on oxidative phosphorylation to sustain the metabolism, meclizine delayed anoxic depolarization onset after middle cerebral artery occlusion. Moreover, the\n              <jats:italic toggle=\"yes\">(S<\/jats:italic>\n              ) enantiomer showed reduced H1 receptor binding, a dose-limiting side effect for the racemate, but retained its effect on mitochondrial respiration.\n              <jats:italic toggle=\"yes\">(S<\/jats:italic>\n              )-meclizine was at least as efficacious as the racemate in delaying anoxic depolarization onset and decreasing infarct volumes after middle cerebral artery occlusion.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Our data identify\n              <jats:italic toggle=\"yes\">(S<\/jats:italic>\n              )-meclizine as a promising new drug candidate with high translational potential as a chemical preconditioning agent for preemptive prophylaxis in patients with high imminent stroke or myocardial infarction risk.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.123.044397","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T09:01:51Z","timestamp":1712221311000},"page":"1370-1380","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanism of Action and Translational Potential of (\n            <i>S<\/i>\n            )-Meclizine in Preemptive Prophylaxis Against Stroke"],"prefix":"10.1161","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0504-0119","authenticated-orcid":true,"given":"Jeong Hyun","family":"Lee","sequence":"first","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (J.H.L., P.H., J.L.S., Y.W., A.D., U.M., C.A.)."},{"name":"Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, South Korea (J.H.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9920-2563","authenticated-orcid":true,"given":"Vishal M.","family":"Gohil","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station (V.M.G., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6383-465X","authenticated-orcid":true,"given":"Pedram","family":"Heidari","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (J.H.L., P.H., J.L.S., Y.W., A.D., U.M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Seidel","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (J.H.L., P.H., J.L.S., Y.W., A.D., U.M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-9508","authenticated-orcid":true,"given":"Mohammad","family":"Zulkifli","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station (V.M.G., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wei","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (J.H.L., P.H., J.L.S., Y.W., A.D., U.M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Ji","sequence":"additional","affiliation":[{"name":"Grace Science, LLC, Menlo Park, CA (Y.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7927-2030","authenticated-orcid":true,"given":"Ali","family":"Daneshmand","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (J.H.L., P.H., J.L.S., Y.W., A.D., U.M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7414-6123","authenticated-orcid":true,"given":"Umar","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (J.H.L., P.H., J.L.S., Y.W., A.D., U.M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-9245","authenticated-orcid":true,"given":"Clary 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