Abstract WP334: Brain Permeable Iron Chelator HBED Improves White Matter Integrity After Traumatic Brain Injury

Abstract

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<0.05). HBED mice also demonstrate a significant decrease in Iba1 expression in the body of the corpus callosum when compared to controls (p<0.05). More testing for the effect of HBED on iron susceptible oligodendrocyte and white matter affected proteins is under currently under investigation. 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).]