Preclinical outcomes of antioxidant therapy in traumatic brain injury-a systematic review

Background: Traumatic brain injury (TBI) is a major cause of cognitive and neurological disability worldwide. Secondary injury processes, including oxidative stress and neuroinflammation, significantly worsen outcomes. Although antioxidant therapies have shown promise in preclinical studies for mitigating oxidative damage, a comprehensive synthesis evaluating their efficacy, mechanisms, and translational potential is lacking. This systematic review addresses this gap by analyzing global preclinical evidence on antioxidant interventions in TBI. Methodology: A systematic literature search was performed in accordance with PRISMA 2020 guidelines across Web of Science, Scopus, and PubMed using the terms “traumatic brain injury” AND “antioxidant.” Retrieved records were deduplicated and screened in two stages: title/abstract review followed by full-text assessment against predefined eligibility criteria. Sixty-one preclinical studies investigating antioxidant interventions in animal models of TBI, reporting outcomes related to oxidative/inflammatory biomarkers, histopathological changes, or functional recovery, were included. Results: Included studies originated mainly from China (31.1 %) and the United States (24.6 %). Rats (63.9 %) and mice (36.1 %) were the predominant animal models, mostly male (84.8 %). The Controlled Cortical Impact (CCI) model was the primary method for inducing TBI (59.7 %). Antioxidants such as resveratrol, astaxanthin, and N-acetylcysteine consistently reduced oxidative stress markers including malondialdehyde (MDA) and increased endogenous antioxidant enzymes like superoxide dismutase (SOD) and catalase (CAT). Histological analyses revealed decreased neuronal degeneration and improved hippocampal integrity. Conclusion: This review synthesizes preclinical evidence on antioxidants in TBI, highlighting mechanistic insights and therapeutic potential. The findings bridge gaps in translational understanding and underscore the need for standardized, sex-balanced, and clinically relevant studies.