{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:38:45Z","timestamp":1789133925069,"version":"build-2803163510"},"reference-count":49,"publisher":"SAGE Publications","issue":"16-18","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"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":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>\n                      To investigate if nimodipine alleviates traumatic brain injury (TBI)-induced neuronal apoptosis and neurological deficits by inhibiting extracellular histone-mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx, mitochondrial damage, and Caspase pathway activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      In vitro, nimodipine significantly reduced histone-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx in cortical neurons, reversed by Ca\n                      <jats:sup>2+<\/jats:sup>\n                      activator A23187. It restored neuronal proliferation (\u21913-(4,5-dimethylthiazol-2-yl)\u22122,5-diphenyltetrazolium bromide, \u2191Ki67+ cells), reduced apoptosis (\u2193Annexin V\/propidium iodide), improved mitochondrial function (\u2191\u0394\u03a8m\/adenosine triphosphate, \u2193reactive oxygen species\/malondialdehyde, \u2191Glutathione Peroxidase), and modulated apoptosis markers (\u2193Bax, \u2191Bcl-2). These effects were blocked by A23187 or Caspase activator AD-2646, which increased Cleaved Caspase-3\/9 and PARP1. Molecular docking confirmed nimodipine-histone binding. Transcriptomics revealed nimodipine reversed histone-induced dysregulation of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signaling, mitochondrial apoptosis, and oxidative stress pathways, with Caspase-3 as a key protein\u2013protein interaction node. In vivo, nimodipine improved spatial memory (Morris maze), neurological function (\u2193modified neurological severity score), and motor coordination (\u2191rotarod) in TBI mice. It reduced brain lesions (2,3,5-triphenyltetrazolium chloride), neuronal loss (hematoxylin and eosin\/Nissl), Ca\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation, and proapoptotic protein expression and restored \u0394\u03a8m. Histone coadministration attenuated these benefits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>\n                      First demonstration that nimodipine directly targets extracellular histone-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx\u2014a key TBI pathology mechanism\u2014preserving mitochondrial integrity and inhibiting the Caspase cascade, extending beyond its known vasodilatory effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Nimodipine mitigates post-TBI neuronal apoptosis and dysfunction by blocking extracellular histone-driven Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload, preventing mitochondrial damage, and suppressing Caspase activation, significantly improving functional recovery.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      43, 869\u2013885.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15230864251376030","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T16:13:24Z","timestamp":1758125604000},"page":"869-885","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Nimodipine Blocks Histone-Induced Calcium Overload to Protect Neurons after Traumatic Brain Injury"],"prefix":"10.1177","volume":"43","author":[{"given":"Wei","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Emergency, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2495-8817","authenticated-orcid":false,"given":"Yunfeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-019-00428-x"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/jir.s363693"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-010-0307-z"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16702"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9020169"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159x17666190927113021"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1479164117723270"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00655.2018"},{"key":"e_1_3_4_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12782"},{"key":"e_1_3_4_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5391"},{"key":"e_1_3_4_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-3816-2_29"},{"key":"e_1_3_4_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19092756"},{"key":"e_1_3_4_14_1","doi-asserted-by":"publisher","DOI":"10.21769\/bioprotoc.3376"},{"key":"e_1_3_4_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202102256"},{"key":"e_1_3_4_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines8100389"},{"key":"e_1_3_4_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-022-01017-8"},{"key":"e_1_3_4_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.09.001"},{"key":"e_1_3_4_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2021.0073"},{"key":"e_1_3_4_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2019.134347"},{"key":"e_1_3_4_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/ta.0b013e318270d595"},{"key":"e_1_3_4_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-024-02753-5"},{"key":"e_1_3_4_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2025.118089"},{"key":"e_1_3_4_24_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/6029237"},{"key":"e_1_3_4_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/bs9.0000000000000226"},{"key":"e_1_3_4_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt674"},{"key":"e_1_3_4_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2024.01.004"},{"key":"e_1_3_4_28_1","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v16.i3.101725"},{"key":"e_1_3_4_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-97-9959-6_10"},{"key":"e_1_3_4_30_1","doi-asserted-by":"publisher","DOI":"10.4274\/tjps.galenos.2020.95776"},{"key":"e_1_3_4_31_1","doi-asserted-by":"publisher","unstructured":"Rai SN Singh S Singh SK. 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