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

Background: Mild head injury associated with long-term functional impairments (i.e., depression, anxiety) is frequently observed among patients who experienced mild traumatic brain injury (mTBI). Moreover, repetitive injuries within a window of vulnerability can lead to exacerbated 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, such as depression. Specifically, in the context of severe brain injury, the p38 MAPK signaling pathway has been identified as a key driver to the inflammatory response, associated with increased microglial activation, proinflammatory cytokines, and synaptic dysfunctions, but its role in the context of mild brain injury remains unclear. As such, this study aimed to investigate whether p38 MAPK drives the inflammatory responses and longer-term deficits following a weight-drop mouse model of repetitive mTBI (rmTBI). Methods: We injected C57/BL6 mice with SB239063, a small molecule p38 MAPK inhibitor, after each of the 5 once-daily weight-drop closed head injuries (CHIs) or sham. We evaluated functional outcomes within 4-weeks after the final CHI and quantified cytokine expressions, microglia reactivity, and transcriptional profiles at 4hr and 4-weeks post final injury. Results: We found that in females, acute inhibition of p38 MAPK attenuated acute inflammatory response comprised of increased cytokine/chemokine expression and microglial activation at 4-hours post injury and longer-term anti-depressive-like behavioral at 4-weeks post injury. However, such effects of p38 inhibition were less obvious in males. On the transcript level, we found that p38 inhibition not only normalized the effects of the brain injury but also upregulated protective genes and pathways associated with recovery and the maintenance of brain homeostasis. Together, these findings support the therapeutic potential of p38 MAPK inhibition following (r)mTBI, indicating the role of p38 MAPK in driving the acute and longer-term consequences post brain injury in a sex dependent manner.