Abstract TP324: Carbon Monoxide Improves Behavioral and Anatomical Outcomes After Brain Trauma in Middle-Aged Female Mice

Abstract

Introduction: Traumatic brain injury (TBI) is a major cause of mortality and long-lasting disabilities. After TBI, secondary brain injury processes trigger. Hypothesis: Carbon monoxide (CO), when given in low concentrations, is postulated to alleviate secondary injury and promote cell survival. This effect is expected to be mediated through the Nrf2 pathway. Methods: In this study, four groups of female mice at the age of 12±2 months old were subjected to controlled-cortical injury (CCI) trauma model (n=13/group). CO or air control were delivered through inhalation to wildtype (WT) and Nrf2 -/- cohorts, for a duration of one hour, and at a rate of 250 ppm. Behavioral assessments through the open field, rotarod, and neurological deficit score tests were performed every day until a 7d endpoint. Results: WT/CO-treated mice show the best behavioral outcomes compared with WT/Air and both Nrf2 -/- mice groups (p<0.05). However, Nrf2 -/- /CO-treated mice have better behavioral outcomes compared with Nrf2 -/- /Air mice group (p<0.05). Nrf2 -/- /Air mice group shows not only the most significantly detrimental behavioral outcome (p<0.05) but also, significantly, the largest cortical injury volume compared with Nrf2 -/- /CO-treated mice and both WT mice groups (p<0.05). The cortical injury volume was not significantly different between both WT groups and Nrf2 -/- /CO-treated mice. Additional investigations of gliosis, edema and oxidative stress after CO administration are in process. Conclusion: Brain tissue that lacks Nrf2 protein and CO gas showed the worst behavioral and cortical injury outcomes. When CO is provided to Nrf2 -/- or WT mice, better outcomes appeared. Even more, WT mice which treated with CO have the most improved outcomes. This influence could partially be mediated through the Nrf2 pathway. Taken together, these findings suggest that CO treatment may be considered as part of therapy for TBI and will open the door for further investigation. [This work was supported in part by grants from the McKnight Brain Research Foundation, Brain and Spinal Cord Injury Research Trust Fund, and AHA33450010, and NIH R21NS095166 (SD).]