{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T20:45:20Z","timestamp":1777927520839,"version":"3.51.4"},"reference-count":127,"publisher":"SAGE Publications","issue":"15-16","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurotrauma"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>\n                    Sex disparities in traumatic brain injury (TBI) remain poorly understood. Previous data suggest that males are more susceptible to acute secondary injury processes and cell death, whereas females are more vulnerable chronically. Additional sex-based differences have been reported depending on injury model\/severity and post-traumatic neurodegeneration. This gap in understanding limits therapy translation. We previously demonstrated sex-based differences in genetic modulation of a key pathway of secondary injury in TBI, sulfonylurea-receptor 1 (SUR1). Glibenclamide (GLI, SUR1-inhibitor) has shown promise in pre-clinical and early clinical studies of TBI and stroke. Here, we evaluated GLI\u2019s modulation of multifaceted TBI outcomes across sex for the first time. In total, 120 mice were randomized to controlled cortical impact (CCI) \u00b1 GLI or vehicle (dimethyl sulfoxide, DMSO). Either vehicle or GLI treatment was administered post-CCI using an intraperitoneal (IP) loading dose (10 \u00b5g\/mouse, 10 min post-TBI), followed by a 7-day subcutaneous maintenance infusion at 0.5 \u00b5L\/h using ALZET mini-osmotic pumps (1007D, Durect Corp.). Mice were tested for cognitive function (Morris water maze, MWM), motor function (rotarod), anxiety (elevated plus maze, EPM), immunofluorescence markers of neurodegeneration (TAU, TDP43), neurogenesis (SOX2, Ki67), angiogenesis (VEGFA), and cerebral blood flow (CBF) to interrogate behavioral, molecular, and physiological effects of TBI and therapy. Different measures within behavioral, immunofluorescence, and CBF outcomes varied across sex, either post-CCI and\/or in response to GLI. Motor impairment had baseline differences across sex post-CCI. In both sexes, behavioral deficits were improved by GLI. The effect of GLI on behavior was moderated by sex, with greater benefit in males versus females, including improved MWM latency (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>treatment*sex_interaction<\/jats:sub>\n                    &lt; 0.0001) and rotarod latency (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>treatment*sex_interaction<\/jats:sub>\n                    = 0.016, revolutions per minute,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>treatment*sex_interaction<\/jats:sub>\n                    = 0.03). Males had increased anxiety post-CCI (EPM); GLI was beneficial across sexes. TDP43 and TAU in several brain regions were increased 72 h post-CCI (males&gt;females, all\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    &lt; 0.0001). These remained markedly elevated only in females by 21 days, whereas TAU in males decreased without treatment. GLI downregulated TDP43 and TAU across sex and brain region (all\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    &lt; 0.01\u20130.0001). In females only, DMSO had similar effects as GLI on TDP43 and TAU. SOX2 was increased in the dentate gyrus (DG) only in males post-CCI (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>72h<\/jats:sub>\n                    &lt; 0.01,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>21d<\/jats:sub>\n                    &lt; 0.001). GLI increased DG SOX2 in females (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>72h<\/jats:sub>\n                    &lt; 0.05,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    <jats:sub>21d<\/jats:sub>\n                    &lt; 0.001). GLI increased VEGFA at 72 h across sexes. CCI reduced CBF acutely in both sexes; in males, GLI improved this by 21 days (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    = 0.031). In females, both GLI and DMSO-vehicle benefited CBF versus untreated-CCI. We demonstrate novel sex-based differences post-CCI and GLI-response across several metrics. TAU was chronically elevated (and responsive to treatment) in females, not males, potentially providing a sex-specific target. DMSO may have previously unrecognized benefits on certain pathways (TAU, CBF) in females. Although GLI has multifaceted benefits across sexes, effects are more pronounced in males. This may have important implications for clinical trial study design and analysis.\n                  <\/jats:p>","DOI":"10.1089\/neu.2024.0232","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T04:54:34Z","timestamp":1749790474000},"page":"1319-1344","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Sexually Dimorphic Responses Reveal Multifaceted Benefits of Glibenclamide in Traumatic Brain Injury"],"prefix":"10.1177","volume":"42","author":[{"given":"Anupama","family":"Rani","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudhanshu P.","family":"Raikwar","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wonsuk","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."},{"name":"Ivy Brain Tumor Center and Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saif","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent A.","family":"Vagni","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keri L.","family":"Janesko-Feldman","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-5075","authenticated-orcid":false,"given":"Shaun W.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."},{"name":"Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Eberle","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaux","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Helm","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Catapano","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin E.","family":"Zusman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashvat","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raemier Anne M.","family":"Javelosa","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Semeon","family":"Afework","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin Audrey","family":"McNally","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Kohanbash","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."},{"name":"Department of Pediatrics, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhivyaa","family":"Rajasundaram","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pittsburgh, Pennsylvania, USA."},{"name":"Division of Health Informatics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael F.","family":"Waters","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Mount Sinai Health System, New York, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Ducruet","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashutosh","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aditya","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Ling","family":"Phuah","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2627-913X","authenticated-orcid":false,"given":"Patrick M.","family":"Kochanek","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Department of Pediatrics, Pittsburgh, Pennsylvania, USA."},{"name":"UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3047-7649","authenticated-orcid":false,"given":"Ruchira M.","family":"Jha","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."},{"name":"Department of Neurosurgery, Barrow Neurological Institute and St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona, USA."},{"name":"Department of Neurology, Barrow Neurological Institute 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