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We investigated whether voluntary running wheel (RW) activity affects epileptogenesis in a mouse model of acquired epilepsy compared to sedentary mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Epilepsy was induced by intra\u2010amygdala kainate causing status epilepticus (SE) in adult male mice. Sham mice were implanted with electrodes and injected with saline, and matched to experimental mice. In the RW\u20101 protocol, SE mice were trained to run for 5\u2009weeks before SE induction and for 6\u2009weeks thereafter. In the RW\u20102 protocol, mice began using RWs 24\u2009h post\u2010SE for 10\u2009weeks. At the end of each protocol, electrocorticography (ECoG) was recorded for 2\u2009weeks (24\/7) in the absence of RWs. Matched sedentary mice were kept in home cages without RWs, subjected to SE, and had ECoG monitored. At the end of experiment, all mice were processed for assessing hippocampal neuronal cell loss (Nissl staining), hilar mossy cells (GluR2\/3 staining), and blood\u2013brain barrier (BBB) damage (serum matrix metalloproteinase\u20109 [MMP\u20109] by enzyme\u2010linked immunosorbent assay). Neuroinflammation (reverse\u2010transcriptase quantitative polymerase chain reaction) and albumin level (western blot) were also measured in the hippocampus of RW\u20101 mice 72\u2009h post\u2010SE, together with serum MMP\u20109.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RW activity in SE mice reduced the incidence of epilepsy (RW\u20101 by 38%; RW\u20102 by 54%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05) and the total time spent in seizures (RW\u20101,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05; RW\u20102,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01) compared to sedentary mice. RW\u20101 SE mice showed reduced average seizure duration (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01), whereas RW\u20102 SE mice showed reduced number of seizures (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01). Reduction in seizure duration was associated with prevention of GluR2\/3\u2010positive mossy cell loss, which occurs in sedentary SE mice (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01 vs sham mice). Seizure duration in epileptic mice was negatively correlated with the number of hilar mossy cells (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01). Preventive RW\u20101 activity reduced SE duration and severity (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05) vs sedentary mice. Aberrant neurogenesis was reduced in the dentate gyrus of SE mice subjected to RWs (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01) vs sedentary mice. Serum MMP\u20109 and brain albumin levels were reduced in SE mice exposed to running activity (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05) compared to sedentary mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Physical exercise reduced seizure burden and neuropathology in mice, offering a strategy to improve disease outcomes after acute brain injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18313","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T10:49:23Z","timestamp":1740134963000},"page":"1718-1733","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Voluntary running wheel activity reduces seizure burden and affords neuroprotection in a mouse model of acquired epilepsy"],"prefix":"10.1111","volume":"66","author":[{"given":"Valentina","family":"Kebede","sequence":"first","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Di Sapia","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9166-8315","authenticated-orcid":false,"given":"Nicole","family":"Tonesi","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5477-2263","authenticated-orcid":false,"given":"Massimo","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Balosso","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Spallaci","sequence":"additional","affiliation":[{"name":"Department of Acute Brain and Cardiovascular Injury Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Craparotta","sequence":"additional","affiliation":[{"name":"Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Pasetto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Bonetto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerardo","family":"Marsella","sequence":"additional","affiliation":[{"name":"Animal Welfare Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Porcu","sequence":"additional","affiliation":[{"name":"Cancer Research UK Cambridge Institute University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Rosati","sequence":"additional","affiliation":[{"name":"Tecniplast S.p.A.  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