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Inflammation during neurobiological recovery is hypothesized to influence susceptibility to poorer outcomes after repetitive mild traumatic brain injury. Here, we investigated whether the inflammatory response during neurobiological recovery is related to susceptibility to increased functional and biological deficits following re-injury. To investigate this, we collected serum 1, 3, 7 or 14 days after mild traumatic brain injury in male Sprague\u2013Dawley rats and measured levels of circulating inflammatory cytokines using the MesoScale Discovery MESO QuickPlex SQ 120MM platform to quantify interferon-gamma, interleukin-1-beta, interleukin-4, interleukin-5, interleukin-6, interleukin-10, interleukin-13, keratinocyte chemoattractant\/human growth-related oncogene and tumour necrosis factor-alpha. Immediately following this blood collection, rats were given a second mild traumatic brain injury to assess associations between cytokine levels at time of second mild traumatic brain injury with behavioural outcomes, neurofilament light levels, and ex vivo diffusion tensor imaging in the 28 days following second injury. After a single mild traumatic brain injury, interleukin-10, interleukin-13, interleukin-4 and tumour necrosis factor-alpha were elevated 3 days post-injury while interleukin-10 and tumour necrosis factor-alpha levels were elevated 14-days post-injury. Furthermore, higher levels of interleukin-6 and interleukin-13 at the time of a second mild traumatic brain injury were associated with a reduced number of acute neurological signs of mild traumatic brain injury following the second injury. There were no other significant correlations between circulating cytokine levels and post-injury outcomes following correction for multiple comparisons. These findings provide initial, hypothesis-generating evidence that higher levels of circulating inflammatory cytokines at the time of a second mild traumatic brain injury may be associated with decreased susceptibility to a second mild traumatic brain injury, highlighting the complex role of inflammation in repeated mild traumatic brain injury.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag019","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T12:38:33Z","timestamp":1769863113000},"source":"Crossref","is-referenced-by-count":0,"title":["Investigating associations between serum inflammatory cytokines at the time of second mild traumatic brain injury with acute neurological signs, axonal injury and behavioural outcomes in male Sprague\u2013Dawley rats"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4927-8438","authenticated-orcid":false,"given":"Justin","family":"Brand","sequence":"first","affiliation":[{"name":"Division of Medical Sciences, University of Victoria , Victoria, BC V8P 5C2 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandy R","family":"Shultz","sequence":"additional","affiliation":[{"name":"Division of Medical Sciences, University of Victoria , Victoria, BC V8P 5C2 ,","place":["Canada"]},{"name":"Department of Neuroscience, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neurology, The Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Centre for Trauma and Mental Health Research, Vancouver Island University , Nanaimo, BC V9R 5S5 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7535-8651","authenticated-orcid":false,"given":"David K","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley L J J","family":"van Emmerik","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mastura","family":"Monif","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neurology, The Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-0160","authenticated-orcid":false,"given":"Brian R","family":"Christie","sequence":"additional","affiliation":[{"name":"Division of Medical Sciences, University of Victoria , Victoria, BC V8P 5C2 ,","place":["Canada"]},{"name":"Island Medical Program, University of British Columbia , Victoria, BC V8P 5C2 ,","place":["Canada"]},{"name":"Department of Psychology, San Diego State University , San Diego, CA 92182 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart J","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Monash University , Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Neurology, The Alfred Hospital , Melbourne, VIC 3004 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William 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