Antioxidant Therapies for Traumatic Brain Injury

Spinal Cord & Brain Injury Research Center, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Journal of the American Society for Experimental NeuroTherapeutics (Impact Factor: 5.05). 01/2010; 7(1):51-61. 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
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    • "Despite the failures of TBI clinical trials to date, progress has been made in identifying the numerous alterations in molecular and cellular processes associated with TBI pathophysiology, including oxidative stress (Hall et al., 2010) and protein aggregation. TBI results in an array of pathophysiological responses and clinical consequences similar to a subset of those observed in PD and other NDDs including accumulation of aggregated synucleins and disturbances in the synuclein metabolism (Smith et al., 2003; Uryu et al., 2007; Beauchamp et al., 2008; Blennow et al., 2012). "
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    ABSTRACT: Synucleins are small prone to aggregate proteins associated with several neurodegenerative diseases (NDDs), however their role in traumatic brain injury (TBI) is an emerging area of investigation. Using in vitro scratch injury model and in vivo mouse weight-drop model we have found that the injury causes alterations in the expression and localization of synucleins near the damaged area. Before injury, α-synuclein is diffuse in the cytoplasm of neurons and γ-synuclein is both in the cytoplasm and nucleus of oligodendrocytes. After the scratch injury of the mixed neuronal and glial culture, α-synuclein forms punctate structures in the cytoplasm of neurons and γ-synuclein is almost completely localized to the nucleus of the oligodendrocytes. Furthermore, the amount of post-translationally modified Met38-oxidized γ-synuclein is increased 3.8 fold 24 hour after the scratch. α- and γ-Synuclein containing cells increased in the initially cell free scratch zone up to 24 hour after the scratch. Intracellular expression and localization of synucleins is also changed in a mouse model of focal closed head injury, using a standardized weight drop device. γ-Synuclein goes from diffuse to punctate staining in a piriform cortex near the amygdala, which may reflect the first steps in the formation of deposits/inclusions. Surprisingly, oxidized γ-synuclein co-localizes with cofilin-actin rods in the thalamus, which are absent in all other regions of the brain. These structures reach their peak amounts 7 days after injury. The changes in γ-synuclein localization are accompanied by injury-induced alterations in the morphology of both astrocytes and neurons.
    Full-text · Article · Oct 2014 · Molecular and Cellular Neuroscience
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    • "As such, the alleviation of oxidative stress is an important therapeutic strategy for the treatment of neurotrauma. However, despite encouraging pre-clinical assessments of numerous antioxidants, there are currently no effective antioxidant strategies for attenuation of ROS production in clinical use following neurotrauma [9]. "
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    ABSTRACT: Red/near-infrared irradiation therapy (R/NIR-IT) delivered by laser or light-emitting diode (LED) has improved functional outcomes in a range of CNS injuries. However, translation of R/NIR-IT to the clinic for treatment of neurotrauma has been hampered by lack of comparative information regarding the degree of penetration of the delivered irradiation to the injury site and the optimal treatment parameters for different CNS injuries. We compared the treatment efficacy of R/NIR-IT at 670 nm and 830 nm, provided by narrow-band LED arrays adjusted to produce equal irradiance, in four in vivo rat models of CNS injury: partial optic nerve transection, light-induced retinal degeneration, traumatic brain injury (TBI) and spinal cord injury (SCI). The number of photons of 670 nm or 830 nm light reaching the SCI injury site was 6.6% and 11.3% of emitted light respectively. Treatment of rats with 670 nm R/NIR-IT following partial optic nerve transection significantly increased the number of visual responses at 7 days after injury (P#0.05); 830 nm R/NIR-IT was partially effective. 670 nm R/NIR-IT also significantly reduced reactive species and both 670 nm and 830 nm R/NIR-IT reduced hydroxynonenal immunoreactivity (P#0.05) in this model. Pre-treatment of light-induced retinal degeneration with 670 nm R/NIR-IT significantly reduced the number of Tunel+ cells and 8-hydroxyguanosine immunoreactivity (P#0.05); outcomes in 830 nm R/NIR-IT treated animals were not significantly different to controls. Treatment of fluid-percussion TBI with 670 nm or 830 nm R/NIR-IT did not result in improvements in motor or sensory function or lesion size at 7 days (P.0.05). Similarly, treatment of contusive SCI with 670 nm or 830 nm R/NIR-IT did not result in significant improvements in functional recovery or reduced cyst size at 28 days (P.0.05). Outcomes from this comparative study indicate that it will be necessary to optimise delivery devices, wavelength, intensity and duration of R/NIR-IT individually for different CNS injury types.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Resveratrol was first acknowledged as an antioxidative molecule in the treatment of CNS diseases and injuries such as ischemic stroke [132], neurodegenerative diseases [133] and TBI [134]. Oxidative stress occurs when the antioxidative machinery in a cell or organism is overwhelmed by the production of reactive oxygen species (ROS), whether from endogenous (increased metabolic rate) or exogenous (pollution , smoking, pesticides) sources. "
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    ABSTRACT: Under normal conditions, most of the central nervous system (CNS) is protected by the blood brain barrier (BBB) from systemic inflammation progression and from the infiltration of immune cells. As a consequence, the CNS developed an original way to provide surveillance, defense and repair, which relies on the complex process of neuroinflammation. Despite tight regulation, neuroinflammation is frequently the cause of irreversible nerve cell loss but it is also where the solution lies. Specific immune crosstalk taking place in the CNS needs to be decoded in order to identify the best therapeutic strategies aimed at helping the CNS restore homeostasis in difficult conditions such as is the case in neurodegenerative disorders. This review deals with the double-edged sword nature of neuroinflammation and the use of resveratrol in various models as one of the most promising therapeutic molecules for preventing the consequences of nerve cell auto-destruction.
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