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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-/- /CO-treated mice have better behavioral outcomes compared with Nrf2 -/- /Air mice group (p-/- /Air mice group shows not only the most significantly detrimental behavioral outcome (p-/- /CO-treated mice and both WT mice groups (p-/- /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).]

Introduction: Traumatic brain injury (TBI) contributes significantly to the overall disabilities and mortality in the United States and worldwide. Many distinct pathophysiological processes follow brain trauma. Iron is postulated to contribute majorly to the secondary cascades after TBI. Therefore, the use of a potent iron chelator like N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid monohydrochloride (HBED) which has higher affinity, better permeability to BBB and longer half-life than most of the commonly used chelators is expected to improve outcomes after TBI. Methods: a controlled-cortical impact model of traumatic brain injury (TBI) was induced in two groups of WT male mice at 4.0±0.5mo of age (n=12/group). Mice were subcutaneously injected with HBED immediately after TBI, then at 12h after, followed by a twice-a-day regimen until the 3d end-point. Results: In addition to the overall anatomical and functional benefits, HBED-treated mice show a significantly thicker, more intact corpus callosum when compared with vehicle control mice (p Conclusion: HBED uniquely protects and maintains the integrity of the corpus callosum. This beneficial effect appears to be mediated through decreasing microglial activation and preserving the anatomical structure of corpus callosum. Such effects are being added to the previously published work on HBED role in mitigating oxidative stress injury and inflammation after TBI. HBED is clinically tested and proven to be safe in humans; thus, further strengthening its possible clinical use after acute brain trauma. [This work was supported in part by grants from the McKnight Brain Research Foundation, Brain and Spinal Cord Injury Research Trust Fund, AHA33450010, and NIH R21NS095166 (SD).]

Introduction: Iron is postulated to contribute to secondary injury after brain trauma through many pathways. Iron participates in the oxidative stress and inflammation processes. The N,N’-Bis(2-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED) is a unique iron chelator as it has ability to cross the blood brain barrier, higher affinity to iron, and longer half-life than most commonly used chelators. Hypothesis: Our study is investigating the efficacy of HBED in protecting brain tissue and improving behavioral outcomes after brain trauma. We are also exploring the histological and biochemical mechanisms behind its beneficial effect. Methods: WT C57BL/6 mice were injected with HBED SQ after TBI and then twice a day till an end point of 3 days. Controlled-cortical impact trauma model was used to inflict injury. Neurobehavioral tests were performed to assess the degree of neurological deficit and short-term recovery over 3 days. We determined cortical Injury volume, hemispheric volume, hippocampal swelling, and corpus callusom volume/thickness. Perls’ and immunohistochemical staining analysis is being performed to assess iron deposits and to inspect microgliosis, oxidative stress injury, and determine the astrocyte roles in regulating brain edema. Results: Thus far, data revealed that HBED treatment significantly decreases motor deficits and improves short term recovery. It also reduces each of cortical injury volume by 36.5±23.5% (p Conclusion: This iron chelator HBED protects against acute traumatic motor deficits and promotes short-term recovery. It reduces cortical injury, hippocampal swelling, and total hemispheric volume after traumatic brain injury. These findings indicate that using HBED in humans may have similar robust effect and ultimately facilitates functional recovery. [This work was supported in part by grants from the McKnight Brain Research Foundation, Brain and Spinal Cord Injury Research Trust Fund, and AHA 33450010, and NIH R21NS095166.]