Antioxidant Therapies in Traumatic Brain Injury

Abstract

Due to a multiplicity of causes provoking traumatic brain injury (TBI), TBI is a highly heterogeneous pathology, characterized by high mortality and disability rates. TBI is an acute neurodegenerative event, potentially and unpredictably evolving into sub-chronic and chronic neurodegenerative events, with transient or permanent neurologic, cognitive, and motor deficits, for which no valid standardized therapies are available. A vast body of literature demonstrates that TBI-induced oxidative/nitrosative stress is involved in the development of both acute and chronic neurodegenerative disorders. Cellular defenses against this phenomenon are largely dependent on low molecular weight antioxidants, most of which are consumed with diet or as nutraceutical supplements. A large number of studies have evaluated the efficacy of antioxidant administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. Points of weakness of preclinical studies are represented by the large variability in the TBI model adopted, in the antioxidant tested, in the timing, dosages, and routes of administration used, and in the variety of molecular and/or neurocognitive parameters evaluated. The analysis of the very few clinical studies does not allow strong conclusions to be drawn on the real effectiveness of antioxidant administration to TBI patients. Standardizing TBI models and different experimental conditions, as well as testing the efficacy of administration of a cocktail of antioxidants rather than only one, should be mandatory. According to some promising clinical results, it appears that sports-related concussion is probably the best type of TBI to test the benefits of antioxidant administration.

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

“…However, additional contributors to oxidative stress, such as NADPH oxidase [57], activated microglia and macrophages during neuroinflammation [58], and an imbalance in iron metabolism [59], have all been shown to participate in ROS overproduction following TBI. RNS formation depends both on NO formation by the three isoforms of nitric oxide synthases (endothelial, eNOS; neuronal, nNOS; and inducible, iNOS) and by the concomitant overproduction of ROS [60]. It has also been shown that microglia, activated as part of the neuroinflammatory response to ROS formation [58], are largely responsible for most of the RNS production in the post-traumatized brain [61].…”

Traumatic Brain Injury: Oxidative Stress and Novel Anti-Oxidants Such as Mitoquinone and Edaravone

“…The different mechanisms involved in oxidative stress can be considered as putative targets for the treatment of TBI. For example, there are compounds involved in inhibiting LP initiation by preventing the formation of ROS and reactive nitrogen species (RNS) such as nitric oxide synthase (NOS) inhibitors [ 35 , 38 , 39 , 40 ]. Another approach is to inhibit enzymes of the AA cascade, like cyclooxygenase and 5-lipoxygenases, which eventually blocks the formation of O 2 ¯.…”

“…Another approach is to inhibit enzymes of the AA cascade, like cyclooxygenase and 5-lipoxygenases, which eventually blocks the formation of O 2 ¯. Cyclooxygenase inhibition by nonsteroidal anti-inflammatory agents like ibuprofen were found to be neuroprotective in TBI models [ 35 , 39 , 40 , 41 ].…”

“…A second indirect approach to inhibit LP initiation involves scavenging radical species like O 2 ¯, OH¯, NO 2 , and CO 3 − to prevent their interaction with fatty acids. For example, the superoxide dismutase (SOD) enzyme was found to scavenge O 2 ¯ [ 35 , 39 , 40 , 42 ] and nitroxide antioxidant (tempol) was shown to scavenge NO 2 and CO 3 − [ 35 , 39 , 40 , 43 ]. The 21-aminosteroid LP inhibitor tirilazad (also known as U74006F) was used in several animal studies and human trials and was found to inhibit free radical-induced LP by scavenging lipid Peroxyl radicals (LOO − ) and to stabilize membranes, which limits the interaction between an LOO – and adjacent fatty acids [ 44 , 45 , 46 , 47 ].…”

“…Vit E can only quench one LOO − and cannot scavenge another LOO − until it is reduced back to its active form by receiving an electron from other endogenous antioxidants such as ascorbic acid (Vit C) or glutathione. This is known as the tripartite antioxidant system [ 35 , 39 , 40 , 48 ]. Other LOO − scavengers include curcumin [ 49 ], resveratrol, melatonin [ 50 ], and lipoic acid [ 51 ].…”