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Blood-Related Toxicity after Traumatic Brain Injury: Potential Targets for Neuroprotection

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Abstract

Emergency visits, hospitalizations, and deaths due to traumatic brain injury (TBI) have increased significantly over the past few decades. While the primary early brain trauma is highly deleterious to the brain, the secondary injury post-TBI is postulated to significantly impact mortality. The presence of blood, particularly hemoglobin, and its breakdown products and key binding proteins and receptors modulating their clearance may contribute significantly to toxicity. Heme, hemin, and iron, for example, cause membrane lipid peroxidation, generate reactive oxygen species, and sensitize cells to noxious stimuli resulting in edema, cell death, and increased morbidity and mortality. A wide range of other mechanisms such as the immune system play pivotal roles in mediating secondary injury. Effective scavenging of all of these pro-oxidant and pro-inflammatory metabolites as well as controlling maladaptive immune responses is essential for limiting toxicity and secondary injury. Hemoglobin metabolism is mediated by key molecules such as haptoglobin, heme oxygenase, hemopexin, and ferritin. Genetic variability and dysfunction affecting these pathways (e.g., haptoglobin and heme oxygenase expression) have been implicated in the difference in susceptibility of individual patients to toxicity and may be target pathways for potential therapeutic interventions in TBI. Ongoing collaborative efforts are required to decipher the complexities of blood-related toxicity in TBI with an overarching goal of providing effective treatment options to all patients with TBI.

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Funding

This work was supported in part by grants from the Brain Aneurysm Foundation, the American Heart Association, and the National Institutes of Health (R21NS095166, NS103036, NS110008), and the Department of Anesthesiology.

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  1. Steven A. Robicsek, Ayon Bhattacharya and Ferenc Rabai contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, College of Medicine, University of Florida, 1275 Center Drive, Biomed Sci J493, Gainesville, FL, 32610, USA

    Steven A. Robicsek, Ayon Bhattacharya, Ferenc Rabai, Krunal Shukla & Sylvain Doré

  2. Departments of Neurosurgery, Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA

    Steven A. Robicsek

  3. Department of Pharmacology, KPC Medical College, West Bengal University of Health Sciences, Kolkata, West Bengal, India

    Ayon Bhattacharya

  4. Departments of Neurology, Psychiatry, Pharmaceutics and Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA

    Sylvain Doré

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Robicsek, S.A., Bhattacharya, A., Rabai, F. et al. Blood-Related Toxicity after Traumatic Brain Injury: Potential Targets for Neuroprotection. Mol Neurobiol 57, 159–178 (2020). https://doi.org/10.1007/s12035-019-01766-8

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