Reduction in Reaction Oxygen Species With Novel Intervention Following TBI in a Large Animal Model
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Neuroscience, Trauma, 2022
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INTRODUCTION: Traumatic brain injury [TBI] is a significant source of morbidity and mortality in the United States, affecting 2.8 million people per year. Lifetime costs following TBI have been estimated as high as $76.5 billion dollars. Despite high costs to society, there are no approved therapeutics. One significant hurdle is the lack of translational large animal platforms in TBI. Generation of mitochondrial reactive oxygen species [mtROS] following TBI impairs complexes in the electron transport chain, in a cycle that further harms mitochondrial function, increasing mtROS. mtROS can influence apoptosis. We examined a novel therapeutic, CMX-2043 - an alpha lipoic acid [ALA] analogue - to see if it could reduce mtROS following TBI in a swine model. METHODS: Yorkshire piglets, n=16, 4-weeks old, were randomized and blinded into sham [5], placebo [6] and treatment [5] groups. Sham animals had surgical incision and anesthesia similar to injured animals. Placebo and treatment pigs received a moderate-severe controlled cortical impact [CCI] injury. Treatment group received 18mg/kg CMX-2043 at 1-hour and 13-hours following injury. 24-hours after injury, animals were sacrificed. Mitochondrial respirometry function was analyzed utilizing ex-vivo brain cortical homogenates. Mitochondria were exposed to a sequence of substrate, uncoupler, inhibitor titrations that interrogate the mitochondrial oxidative phosphorylation system. Respirometry control ratios [RCR] were used as an overall measure of mitochondrial health. Measurements of mtROS were assessed simultaneously with respirometry measurements by an O2k-Fluorescence LED2-Module (Oroboros) utilizing an Amplex UltraRed assay. ELISA was performed to measure 4-HNE, a downstream marker of lipid peroxidation. RESULTS: Markers of mtROS and lipid peroxidation were significantly decreased in animals treated with CMX-2043 as compared to placebo (mtROS: 8.28+/-1.47 vs. 18.77+/-1.58, p < 0.05; 4-HNE 0.287+/-0.051 vs. 1.432+/-0.59, p < 0.05). CMX-2043 animals demonstrated significantly higher mitochondrial respiration compared to placebo; RCR (11.61+/-2.284 vs. 6.006+/-0.2678, p < 0.05). CONCLUSIONS: Treatment with CMX-2043 demonstrated a statistically significant reduction in mtROS, lipid peroxidation and improved mitochondrial function at 24-hours post-TBI in a large animal model.
Meta Tag
Content Type Presentation
Knowledge Area Neuroscience
Knowledge Area Trauma
Knowledge Level Advanced
Membership Level Select
Tag Traumatic Brain Injury TBI
Tag Trauma
Year 2022
traumatic brain injury
brain healing
animal models


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