{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:46Z","timestamp":1790899246031,"version":"4.1.0"},"reference-count":7,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>\n              Inhibition of brain NKCC1 (Na\n              <jats:sup>+<\/jats:sup>\n              -K\n              <jats:sup>+<\/jats:sup>\n              -Cl\n              <jats:sup>\u2212<\/jats:sup>\n              cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>Large-vessel transient ischemic stroke in normotensive C57BL\/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)\u2013induced hypertensive C57BL\/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by \u224840% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II\u2013induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.118.024287","type":"journal-article","created":{"date-parts":[[2019,3,13]],"date-time":"2019-03-13T09:01:45Z","timestamp":1552467705000},"page":"1021-1025","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["A Novel Na\n            <sup>+<\/sup>\n            -K\n            <sup>+<\/sup>\n            -Cl\n            <sup>\u2212<\/sup>\n            Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke"],"prefix":"10.1161","volume":"50","author":[{"given":"Huachen","family":"Huang","sequence":"first","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Department of Neurology, First Affiliate Hospital, Harbin Medical University, Heilongjiang, China (H.H., Z.Z.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Iqbal H.","family":"Bhuiyan","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Jiang","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Song","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhya","family":"Shankar","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taraneh","family":"Taheri","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Schreppel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Vienna, Austria (P.S., M.H., T.E.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hintersteininger","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Vienna, Austria (P.S., M.H., T.E.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (S.-S.Y., S.-H.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hua","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (S.-S.Y., S.-H.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley J.","family":"Molyneaux","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliate Hospital, Harbin Medical University, Heilongjiang, China (H.H., Z.Z.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Erker","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Vienna, Austria (P.S., M.H., T.E.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Sun","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1370-5"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.14336\/ad.2018.0928"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24124"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16675368"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13346"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(01)02321-9"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01543"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.118.024287","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T15:33:13Z","timestamp":1715614393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.118.024287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4]]},"references-count":7,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1161\/STROKEAHA.118.024287"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.118.024287","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4]]},"assertion":[{"value":"2018-07-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}