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Engineered dual antioxidant enzymes complexes targeting ICAM-1 on brain endothelium reduces brain injury associated neuroinflammation.
Leonard, Brian
Leonard, Brian
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2024-08
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Pathology
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https://doi.org/10.34944/kgvn-1z22
Abstract
The neuroinflammatory cascade triggered by traumatic brain injury represents a clinically important point for therapeutic intervention. Neuroinflammation generates oxidative stress in the form of high-energy reactive oxygen and nitrogen species, which are key mediators of TBI pathology. The role of the blood-brain barrier is essential for proper neuronal function and is vulnerable to oxidative stress. Results herein explores the notion that attenuating oxidative stress at the vasculature after TBI may result in improved BBB integrity and neuroprotection. Utilizing amino-chemistry, a biological construct (designated as dual-conjugate for short) was generated by covalently binding two antioxidant enzymes (superoxide dismutase 1 and catalase) to antibodies specific for ICAM-1. Bioengineering of the conjugate preserved its targeting and enzymatic functions as evaluated by real-time bioenergetic measurements (via the Seahorse-XF platform) in brain endothelial cells exposed to increasing concentrations of hydrogen peroxide or a superoxide anion donor. Results showed that the dual-conjugate effectively mitigated the mitochondrial stress due to oxidative damage. Furthermore, dual-conjugate administration also improved BBB and endothelial protection under oxidative insult in an in-vitro model of TBI utilizing a software controlled stretching device that induces a 20% in mechanical strain on the endothelial cells. Additionally, the dual-conjugate was also effective in reducing indices of neuroinflammation in the controlled cortical impact CCI-TBI animal model. Thus, these studies provide proof-of-concept that targeted dual antioxidant biologicals may offer a means to regulate oxidative stress associated cellular damage during neurotrauma.
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