Carnosic Acid Improves Outcome after Repetitive Mild Traumatic Brain Injury

In the majority of cases, the cognitive and behavioral impairments resulting from a mild traumatic brain injury (TBI) (also referred to as concussion) wane within days to weeks. In contrast, these impairments can persist for months to years after repetitive mild TBI (rmTBI). The cellular and molecular mechanisms underlying these impairments are not well understood. In the present study, we examined the consequences of rmTBI (three weight drops each separated by 72 h) on brain tissue respiration, pathology, and cognitive performance in mice. The transcription factor nuclear factor-erythroid 2-realted factor 2 (Nrf2) has been demonstrated to enhance the expression of numerous cytoprotective genes. Carnosic acid (CA) has been shown to activate Nrf2 and suppress the proinflammatory transcription factor nuclear factor kappa B (NF-κB). Because contemporaneous activation of cytoprotective genes and inhibition of proinflammatory genes can be beneficial, we questioned whether CA can be used to mitigate the pathobiology of rmTBI. The rmTBI increased hippocampal adenosine triphosphate-linked tissue respiration and proton leak that were unaffected by CA treatment. The rmTBI also caused significant motor and cognitive dysfunction, as tested using the foot fault, Barnes maze, and novel object recognition tasks. These impairments occurred in the absence of visible neuronal or dendritic loss. Post-rmTBI administration of CA significantly improved motor and cognitive function, and decreased Gfap and Iba1 immunoreactivities within white matter tracks. Taken together, these results show that rmTBI can cause cognitive impairments in the absence of overt neuronal pathologies, and post-injury treatment with CA can lessen some of these impairments.