{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:29:45Z","timestamp":1792045785142,"version":"4.4.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2009,5]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background and Purpose\u2014<\/jats:italic>\n            <\/jats:bold>\n            The identification of a neuroprotective drug for stroke remains elusive. Given that mitochondria play a key role both in maintaining cellular energetic homeostasis and in triggering the activation of cell death pathways, we evaluated the efficacy of newly identified inhibitors of cytochrome c release in hypoxia\/ischemia induced cell death. We demonstrate that methazolamide and melatonin are protective in cellular and in vivo models of neuronal hypoxia.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods\u2014<\/jats:italic>\n            <\/jats:bold>\n            The effects of methazolamide and melatonin were tested in oxygen\/glucose deprivation\u2013induced death of primary cerebrocortical neurons. Mitochondrial membrane potential, release of apoptogenic mitochondrial factors, pro\u2013IL-1\u03b2 processing, and activation of caspase -1 and -3 were evaluated. Methazolamide and melatonin were also studied in a middle cerebral artery occlusion mouse model. Infarct volume, neurological function, and biochemical events were examined in the absence or presence of the 2 drugs.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            Methazolamide and melatonin inhibit oxygen\/glucose deprivation\u2013induced cell death, loss of mitochondrial membrane potential, release of mitochondrial factors, pro\u2013IL-1\u03b2 processing, and activation of caspase-1 and -3 in primary cerebrocortical neurons. Furthermore, they decrease infarct size and improve neurological scores after middle cerebral artery occlusion in mice.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            We demonstrate that methazolamide and melatonin are neuroprotective against cerebral ischemia and provide evidence of the effectiveness of a mitochondrial-based drug screen in identifying neuroprotective drugs. Given the proven human safety of melatonin and methazolamide, and their ability to cross the blood-brain-barrier, these drugs are attractive as potential novel therapies for ischemic injury.\n          <\/jats:p>","DOI":"10.1161\/strokeaha.108.540765","type":"journal-article","created":{"date-parts":[[2009,3,20]],"date-time":"2009-03-20T01:57:25Z","timestamp":1237514245000},"page":"1877-1885","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":133,"title":["Methazolamide and Melatonin Inhibit Mitochondrial Cytochrome C Release and Are Neuroprotective in Experimental Models of Ischemic Injury"],"prefix":"10.1161","volume":"40","author":[{"given":"Xin","family":"Wang","sequence":"first","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan E.","family":"Figueroa","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina G.","family":"Stavrovskaya","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C.","family":"Sirianni","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur L.","family":"Day","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce S.","family":"Kristal","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Friedlander","sequence":"additional","affiliation":[{"name":"From the Neuroapoptosis Laboratory (X.W., B.E.F., Y.Z., A.C.S., S.Z., R.M.F.), Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Mass; Department of Neurosurgery (I.G.S., A.L.D., B.S.K.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, 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