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Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL\/6J mice. We observed a significant elevation of Na+\/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.<\/jats:p>","DOI":"10.3390\/antiox13070836","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T18:17:32Z","timestamp":1721067452000},"page":"836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NHE1 Protein in Repetitive Mild TBI-Mediated Neuroinflammation and Neurological Function Impairment"],"prefix":"10.3390","volume":"13","author":[{"given":"John P.","family":"Bielanin","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-6665","authenticated-orcid":false,"given":"Shamseldin A. H.","family":"Metwally","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena C. M.","family":"Oft","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya S.","family":"Paruchuri","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Okan","family":"Capuk","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D.","family":"Pennock","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7200-5922","authenticated-orcid":false,"given":"Shanshan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,13]]},"reference":[{"key":"ref_1","unstructured":"Bagalman, E. 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