{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:14:48Z","timestamp":1790428488117,"version":"4.1.0"},"reference-count":39,"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":[[2011,4]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>Glucocorticoids potently stabilize the blood\u2013brain barrier and ameliorate tissue edema in certain neoplastic and inflammatory disorders of the central nervous system, but they are largely ineffective in patients with acute ischemic stroke. The reasons for this discrepancy are unresolved.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>\n              To address the molecular basis for the paradox unresponsiveness of the blood\u2013brain barrier during hypoxia, we used murine brain microvascular endothelial cells exposed to O\n              <jats:sub>2<\/jats:sub>\n              \/glucose deprivation as an in vitro model. In an in vivo approach, mice were subjected to transient middle cerebral artery occlusion to induce brain infarctions. Blood\u2013brain barrier damage and edema formation were chosen as surrogate markers of glucocorticoid sensitivity in the presence or absence of proteasome inhibitors.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>\n              O\n              <jats:sub>2<\/jats:sub>\n              \/glucose deprivation reduced the expression of tight junction proteins and transendothelial resistance in murine brain microvascular endothelial cells in vitro. Dexamethasone treatment failed to reverse these effects during hypoxia. Proteasome-dependent degradation of the glucocorticoid receptor impaired glucocorticoid receptor transactivation thereby preventing physiological glucocorticoid activity. Inhibition of the proteasome, however, fully restored the blood\u2013brain barrier stabilizing properties of glucocorticoid during O\n              <jats:sub>2<\/jats:sub>\n              \/glucose deprivation. Importantly, mice treated with the proteasome inhibitor Bortezomib in combination with steroids several hours after stroke developed significantly less brain edema and functional deficits, whereas respective monotherapies were ineffective.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>We for the first time show that inhibition of the proteasome can overcome glucocorticoid resistance at the hypoxic blood\u2013brain barrier. Hence, combined treatment strategies may help to combat stroke-induced brain edema formation in the future and prevent secondary clinical deterioration.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.110.592238","type":"journal-article","created":{"date-parts":[[2011,2,18]],"date-time":"2011-02-18T04:20:04Z","timestamp":1298002804000},"page":"1081-1089","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":80,"title":["Glucocorticoid Insensitivity at the Hypoxic Blood\u2013Brain Barrier Can Be Reversed by Inhibition of the Proteasome"],"prefix":"10.1161","volume":"42","author":[{"given":"Christoph","family":"Kleinschnitz","sequence":"first","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinga","family":"Blecharz","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Kahles","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Schwarz","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kraft","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"G\u00f6bel","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven G.","family":"Meuth","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Burek","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Thum","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Stoll","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"F\u00f6rster","sequence":"additional","affiliation":[{"name":"From the Department of Neurology (C.K., G.S., T.S., P.K.) University of W\u00fcrzburg, W\u00fcrzburg, Germany; the Department of Anesthesia and Critical Care (K.B., M.B., C.F.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Weill Cornell Medical College (T.K.), New York, NY; the Department of Neurology\u2013Inflammatory Disorders of the Nervous System and Neuro-oncology (K.G., S.G.M.), University of M\u00fcnster, M\u00fcnster, Germany; and Hannover Medical School (T.T.), IFB, Institute for Molecular and Translational..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1159\/000116232"},{"key":"e_1_3_4_3_2","first-page":"315","article-title":"Role of dexamethasone in the outcome from acute stroke","volume":"37","author":"Kumar N","year":"1989","unstructured":"Kumar N, Jain S, Maheshwari MC. Role of dexamethasone in the outcome from acute stroke. J Assoc Physicians India. 1989;37:315\u2013317.","journal-title":"J Assoc Physicians India"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.0000105930.29558.db"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.292.6512.21"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.0000105931.81723.26"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.107.490193"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90237-7"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2008.08.011"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106033200"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2001.tb01064.x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2001-0347"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1177\/1073858408327809"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600298"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-249078"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052458"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.108.526673"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.17.3.472"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.084038"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(88)90310-9"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/glia.20938","article-title":"Collateral neuronal apoptosis in CNS gray matter during an oligodendrocyte-directed CD8(+) T cell attack","volume":"58","author":"Gobel K","year":"2010","unstructured":"Gobel K, Melzer N, Herrmann AM, Schuhmann MK, Bittner S, Ip CW, Hunig T, Meuth SG, Wiendl H. Collateral neuronal apoptosis in CNS gray matter during an oligodendrocyte-directed CD8(+) T cell attack. Glia. 2010;58:469\u2013480.","journal-title":"Glia"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2008.10.006"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.240470407"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.108.534644"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-008-0424-9"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2005.02.006"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.106385"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.4.2250"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.22.1.11"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1080\/09687680210129236"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.02.012"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21549"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060693"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.11.133"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23203"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.06799"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(98)80007-5"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1159\/000096966"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.03.018"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.109.577288"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.110.592238","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T14:37:18Z","timestamp":1715611038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.110.592238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,4]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2011,4]]}},"alternative-id":["10.1161\/STROKEAHA.110.592238"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.110.592238","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,4]]},"assertion":[{"value":"2010-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-11-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-02-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}