Trehalose: A promising new treatment for traumatic brain injury? A systematic review of animal evidence

•Trehalose was shown to improve both motor and cognitive outcomes in TBI-affected mice, as demonstrated by improved performance.•Trehalose altered the pathways of secondary injury following TBI, including brain metal dyshomeostasis (zinc, copper, and iron), mitochondrial dysfunction, decreased autophagy, neuroinflammation, and decreased neurotrophic factors.•Trehalose elevated markers of synaptic integrity and neurogenesis, such as synaptophysin, doublecortin, and BDNF, in specific brain regions. TBI is a major global health issue due to its high morbidity and mortality rates. Persistent neurodegeneration following secondary brain injuries is a significant concern. Trehalose, a naturally occurring disaccharide, has shown potential therapeutic effects in preclinical TBI models. This study systematically reviews the preclinical and clinical data on trehalose as a potential TBI treatment. We conducted a systematic review of trehalose’s role in TBI treatment following PRISMA guidelines. Our search spanned from the inception of PubMed, EMBASE, SCOPUS, and Web of Science until August 2023. Google Scholar was also manually searched. The quality of the studies was assessed using SYRCLE’s risk of bias tool for animal studies. Out of sixty-six records reviewed, four animal studies were included. These studies indicated that trehalose enhanced motor and cognitive functions, reduced oxidative damage and inflammation, regulated metal dyshomeostasis, increased neurotrophic factors and synaptic proteins, and improved autophagy and mitochondrial function in mouse/rat TBI models. However, a significant risk of bias was noted. Trehalose demonstrates potential as a TBI treatment. However, more rigorous, and comprehensive research is needed to confirm its safety and efficacy in humans.