Antioxidant Therapies for Traumatic Brain Injury

Article (PDF Available)inJournal of the American Society for Experimental NeuroTherapeutics 7(1):51-61 · January 2010with49 Reads
DOI: 10.1016/j.nurt.2009.10.021 · Source: PubMed
Free radical-induced oxidative damage reactions, and membrane lipid peroxidation (LP), in particular, are among the best validated secondary injury mechanisms in preclinical traumatic brain injury (TBI) models. In addition to the disruption of the membrane phospholipid architecture, LP results in the formation of cytotoxic aldehyde-containing products that bind to cellular proteins and impair their normal functions. This article reviews the progress of the past three decades in regard to the preclinical discovery and attempted clinical development of antioxidant drugs designed to inhibit free radical-induced LP and its neurotoxic consequences via different mechanisms including the O(2)(*-) scavenger superoxide dismutase and the lipid peroxidation inhibitor tirilazad. In addition, various other antioxidant agents that have been shown to have efficacy in preclinical TBI models are briefly presented, such as the LP inhibitors U83836E, resveratrol, curcumin, OPC-14177, and lipoic acid; the iron chelator deferoxamine and the nitroxide-containing antioxidants, such as alpha-phenyl-tert-butyl nitrone and tempol. A relatively new antioxidant mechanistic strategy for acute TBI is aimed at the scavenging of aldehydic LP byproducts that are highly neurotoxic with "carbonyl scavenging" compounds. Finally, it is proposed that the most effective approach to interrupt posttraumatic oxidative brain damage after TBI might involve the combined treatment with mechanistically complementary antioxidants that simultaneously scavenge LP-initiating free radicals, inhibit LP propagation, and lastly remove neurotoxic LP byproducts.

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Available from: Ayman Mustafa, Aug 31, 2014
    • "TBIs result from a primary injury induced by an external force to the brain, such as direct impact, acceleration/deceleration or blast. The primary injury initiates a secondary pathophysiological cascade, which is characterized by excitotoxicity, the generation of free radicals and lipid peroxidation [22], mitochondrial dysfunction [23], swelling and loss of astrocytes [13], axonal swelling [24] and neuronal injury [25]. Secondary injury is associated with inflammatory response and alterations in both metabolism and cerebral blood flow [26], axonal lysis and breakdown with parenchymal accumulation of tau and amyloid beta (Aβ) protein [27], demyelination [28] and subsequent axonal degeneration [29] and programmed neuronal death through a caspase-3 activation mechanism [25]. "
    [Show abstract] [Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is one of the leading causes of death and disability around the world. The lack of validated biomarkers for TBI is a major impediment to developing effective therapies and improving clinical practice, as well as stimulating much work in this area. In this review, we focus on different settings of TBI management where blood or cerebrospinal fluid (CSF) biomarkers could be utilized for predicting clinically-relevant consequences and guiding management decisions. Requirements that the biomarker must fulfill differ based on the intended context of use (CoU). Specifically, we focus on fluid biomarkers in order to: (1) identify patients who may require acute neuroimaging (cranial computerized tomography (CT) or magnetic resonance imaging (MRI); (2) select patients at risk for secondary brain injury processes; (3) aid in counseling patients about their symptoms at discharge; (4) identify patients at risk for developing postconcussive syndrome (PCS), posttraumatic epilepsy (PTE) or chronic traumatic encephalopathy (CTE); (5) predict outcomes with respect to poor or good recovery; (6) inform counseling as to return to work (RTW) or to play. Despite significant advances already made from biomarker-based studies of TBI, there is an immediate need for further large-scale studies focused on identifying and innovating sensitive and reliable TBI biomarkers. These studies should be designed with the intended CoU in mind.
    Full-text · Article · Oct 2016
    • "The neuropathological changes observed during neuronal injury, trauma or stroke, have all been ascribed to an enhancement of oxidative stress which in turn induces lipid peroxidation, protein and DNA oxidation (Hall et al., 2010; Hall, 2011; Lin and Lee, 2009). When administered to rats kainic acid (KA), an agonist of the ionotropic glutamate receptor, causes excessive release of glutamate and consequently produces severe brain damage via N-methyl-D-aspartate (NMDA) receptor activation. "
    File · Dataset · Jun 2016
    • "Many cells contain both CAT and GPx, while the brain GPx seems to be the major importance [63]. Vitamin C, a water soluble antioxidant is the most important free radical scavenger in extracellular fluids, trapping radicals in the aqueous phase and protects biomembranes from peroxidative damage [64]. Moreover, Vitamin E is a potent lipid soluble antioxidant in biological systems with the ability to directly quench free radicals and function as membrane stabilizer [16]. "
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