Triplett, S. E. | Search bioRxiv

bioRxiv2026

Neuronal p38α knockout protects against neurological consequences following repetitive mild traumatic brain injury

Mild traumatic brain injuries (mTBI) can substantially impact quality of life, and repetitive mTBIs (rmTBI) can amplify injury effects compared to a single injury. However, effective clinical treatments remain elusive, largely due to an incomplete understanding of the underlying injury mechanisms. Neuroinflammation has emerged as a key contributor to worse functional outcomes after mTBI/rmTBI. While microglia are traditionally viewed as primary mediators of post-injury inflammation, accumulating evidence suggests neurons play an immunomodulatory role in initiating the rmTBI inflammatory cascade through activation of intracellular proinflammatory pathways like p38 MAPK and secretion of cytokines that, in turn, stimulate microglial activation. Here, we tested whether inducible neuronal p38 knockout protects against functional, immune, and cerebrovascular consequences of a weight-drop closed head injury model of rmTBI. A battery of functional assays was conducted 4 weeks post-injury, and tissues were collected at both 4 hours and 4 weeks following final CHI. In males, neuronal p38 knockout protected against injury-induced depressive-like behavior, hyperactivity, synaptic loss, microglial reactivity, cytokine upregulation, and reduction in cerebral blood flow. In females, neuronal p38 knockout protected against risk-taking behavior and partially protected against cytokine upregulation but had limited effect on microglial reactivity and cerebral blood flow. Together, these findings identify neuronal p38 as a sex-dependent driver of rmTBI-associated neurological consequences, and they support neuronal p38-immune signaling as a mechanistically relevant therapeutic target for future studies.

neuroscience↗

bioRxiv2025

Inhibition of p38 MAPK after repetitive mild TBI ameliorates immune signaling and behavioral deficits

BackgroundMild traumatic brain injury (mTBI) can cause long-term functional impairments, and repetitive mTBIs within a window of vulnerability can exacerbate these consequences compared to a single mTBI. However, current interventions for mTBI focus on alleviating symptoms, rather than targeting underlying mechanisms. Following the initial mechanical impact, increasing evidence suggests that the brain undergoes an inflammatory cascade consisting of pro-inflammatory intracellular signaling pathways and production of cytokines, ultimately leading to chronic neuroinflammation and persistent neurological deficits. Prior work in severe traumatic brain injury has shown that the p38 MAPK signaling pathway is a key regulator of microglial activation, proinflammatory cytokines, and synaptic dysfunction, but its role in the context of mTBI remains unclear. As such, this study aimed to determine if inhibition of p38 MAPK would attenuate the inflammatory response and longer-term functional deficits following a weight-drop mouse model of repetitive mTBI. MethodsC57BL/6J male and female mice were injected with a small molecule p38 MAPK inhibitor (SB239063) after each of 5 once-daily weight-drop closed head injuries (CHIs) or sham injuries. Functional outcome was assessed at 4-weeks post injury. Protein and transcriptional alterations associated with the immune response, synaptic function, microglial phenotype, and functional outcomes were assessed at both 4-hours and 4-weeks after the final CHI. ResultsIn females, acute inhibition of p38 MAPK attenuated i) cytokine expression and microglial reactivity at 4-hours post injury and ii) antidepressive-like behavior and synaptic loss at 4-weeks post injury. In males, p38 MAPK inhibition also attenuated microglial reactivity and up-regulation of specific cytokines, although changes in functional outcomes did not reach significance. Interestingly, bulk RNAseq analysis in both sexes showed that acute p38 MAPK inhibition both normalized the effects of injury and upregulated protective genes and pathways associated with recovery and maintenance of brain homeostasis. Together, these findings suggest a role for p38 MAPK in driving the acute and longer-term consequences post repetitive mTBI in a sex-dependent manner, and they suggest therapeutic potential of p38 MAPK inhibition. To our knowledge, this work is the first to investigate the effects of small molecule inhibitor SB239063 as a potential therapeutic treatment administrated following rmTBI.

molecular biology↗