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In a previous experiment, we found that fingolimod promoted recovery after controlled cortical impact injury (CCI) by modulating inflammation around brain lesions. However, it remains unclear whether fingolimod can also attenuate DBI because of its different injury mechanisms. Furthermore, whether fingolimod has additional underlying effects on repairing DBI is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The impact acceleration model of DBI was established in adult Sprague\u2013Dawley rats. Fingolimod (0.5\u2009mg\/kg) was administered 0.5, 24, and 48\u2009h after injury for 3 consecutive days. Immunohistochemistry, immunofluorescence analysis, cytokine array, and western blotting were used to evaluate inflammatory cells, inflammatory factors, AQP4 polarization, apoptosis in brain cells, and the accumulation of APP after DBI in rats. To evaluate the function of the glymphatic system (GS), a fluorescent tracer was injected into the cistern. The neural function of rats with DBI was evaluated using various tests, including the modified neurological severity score (mNSS), horizontal ladder\u2010crossing test, beam walking test, and tape sensing and removal test. Brain water content was also measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fingolimod administration for 3 consecutive days could reduce the levels of inflammatory cytokines, neutrophil recruitment, microglia, and astrocyte activation in the brain following DBI. Moreover, fingolimod reduced apoptotic protein expression, brain cell apoptosis, brain edema, and APP accumulation. Additionally, fingolimod inhibited the loss of AQP4 polarization, improved lymphatic system function, and reduced damage to nervous system function. Notably, inhibiting the GS weakened the therapeutic effect of fingolimod on the neurological function of rats with DBI and increased the accumulation of APP in the brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In brief, these findings suggest that fingolimod alleviates whole\u2010brain inflammation and GS system damage after DBI and that inhibiting the GS could weaken the positive effect of fingolimod on nerve function in rats with DBI. Thus, inhibiting inflammation and regulating the GS may be critical for the therapeutic effect of fingolimod on DBI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.14669","type":"journal-article","created":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:23:41Z","timestamp":1709943821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Fingolimod improves diffuse brain injury by promoting\n                    <scp>AQP4<\/scp>\n                    polarization and functional recovery of the glymphatic system"],"prefix":"10.1111","volume":"30","author":[{"given":"Dongyi","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Tianjin Medical University General Hospital  Tianjin China"},{"name":"Tianjin Neurological Institute, Key Laboratory of Post Neuro\u2010injury Neuro\u2010repair and Regeneration in Central Nervous System, State Key Laboratory of Experimental Hematology Ministry of Education  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tianjin Medical University General Hospital  Tianjin China"},{"name":"Tianjin Neurological Institute, Key Laboratory of Post Neuro\u2010injury Neuro\u2010repair and Regeneration in Central Nervous System, State Key Laboratory of Experimental Hematology Ministry of Education  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Tianjin Medical University General Hospital  Tianjin China"},{"name":"Tianjin Neurological Institute, Key Laboratory of Post Neuro\u2010injury Neuro\u2010repair and Regeneration in Central Nervous System, State Key Laboratory of Experimental Hematology Ministry of Education  Tianjin 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