Inhibition of p38 MAPK after repetitive mTBI ameliorates immune signaling and functional deficits.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can lead to long-term neurological impairments. Following mechanical impact, increasing evidence suggests that the brain undergoes an inflammatory cascade, leading to chronic neuroinflammation and persistent neurological deficits. While the p38 MAPK signaling pathway is implicated in severe TBI, its role in rmTBI is unclear. This study investigated whether small molecule inhibition of p38 MAPK with SB239063 reduces inflammatory response and functional deficits after repetitive mTBI in a mouse weight-drop model. In females, p38 MAPK inhibition reduced synaptic loss, cytokine upregulation, microglial reactivity, functional deficits, and transcript alterations while upregulating protective pathways. In males, p38 MAPK inhibition attenuated microglial changes and transcript alterations but had limited functional effects. Together, these findings suggest the role of p38 MAPK in driving injury consequences in a sex-dependent manner and highlight therapeutic potential for p38 MAPK inhibition after repetitive mTBI.