Traumatic brain injury (TBI) is a major health concern worldwide and is classified based on severity into mild, moderate, and severe. The mechanical injury in TBI leads to a metabolic and ionic imbalance, which eventually leads to excessive production of reactive oxygen species (ROS) and a state of oxidative stress. To date, no drug has been approved by the food and drug administration (FDA) for the treatment of TBI. Nevertheless, it is thought that targeting the pathology mechanisms would alleviate the consequences of TBI. For that purpose, antioxidants have been considered as treatment options in TBI and were shown to have a neuroprotective effect. In this review, we will discuss oxidative stress in TBI, the history of antioxidant utilization in the treatment of TBI, and we will focus on two novel antioxidants, mitoquinone (MitoQ) and edaravone. MitoQ can cross the blood brain barrier and cellular membranes to accumulate in the mitochondria and is thought to activate the Nrf2/ARE pathway leading to an increase in the expression of antioxidant enzymes. Edaravone is a free radical scavenger that leads to the mitigation of damage resulting from oxidative stress with a possible association to the activation of the Nrf2/ARE pathway as well.

: Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on pro-inflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.

Background: Traumatic Brain Injury (TBI) is the most prevalent of all head injuries, and based on the severity of the injury, it may result in chronic neurologic and cognitive de cits. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a bene cial or detrimental role in TBI depending on their state of activation and duration.Methods: In the present study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color ow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue.Results: We characterized several microglial phenotypes and their association with cognitive de cits. TBI results in a spatiotemporal increase in highly activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury.Conclusions: These observations could de ne therapeutic windows and accelerate translational research to improve patient outcomes.

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