• Saher Khalaf, Abdullah Shafique Ahmad, K V D Ranga Chamara, and Sylvain Doré.
• 1 Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida , Gainesville, Florida.
• J. Neurotrauma. 2018 Jul 25; 36 (1): 435343-53.

AbstractIron is postulated to contribute to secondary injury after brain trauma through various pathways including oxidative stress and inflammation. Therefore, one goal is to limit iron toxicity by either directly limiting iron activity, or limiting the secondary cascade mediated by iron, therefore rescuing the brain from damage after trauma. The N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid monohydrochloride (HBED) is a unique iron chelator that has the ability to cross the intact blood-brain barrier; it has a higher affinity to iron, and it has a longer half-life than most commonly used chelators. A controlled-cortical impact model of traumatic brain injury (TBI) was induced in mice. Mice were subcutaneously injected with HBED immediately after TBI, then at 12 h after, followed by a twice-a-day regimen until an end-point of 3 days. Neurobehavioral tests were performed daily. Cortical injury volume, hemispheric enlargement, and hippocampal swelling were quantified. Perls' iron immunostaining along with markers of gliosis, oxidative stress, and aquaporin (AQP) 4 were also performed. Data revealed that HBED treatment significantly decreases motor deficits and improves recovery after TBI. It also reduces cortical injury volume by 36.6 ± 6.8% (p < 0.001), hippocampal swelling by 23.4 ± 3.8% (p < 0.05), and total hemispheric volume by 13.3 ± 2.7% (p < 0.01). These effects are related to a reduction in microgliosis and oxidiative stress markers in the impacted corpus callosum area by 39.8 ± 7.3%, and by 80.5 ± 0.8% (p < 0.05), respectively. AQP4 staining is also attenuated in the hippocampus of HBED-treated mice. Therefore, our results suggest that HBED should be considered as a therapeutic tool to facilitate the recovery process following brain trauma.

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