BACKGROUND: Traumatic brain injury (TBI) is a major health concern, often resulting in significant brain damage and functional impairments. A key contributing factor to TBI-induced neuronal injury is the overactivation of AMPA glutamate receptors, leading to an increased influx of calcium and zinc ions. This study investigates the neuroprotective potential of l-theanine, known for its antioxidant potential and ability to enhance glutathione synthesis, against hippocampal damage in a TBI rat model. METHODS: Rats subjected to TBIs were treated with two dosages of l-theanine (100 and 200 mg/kg) and an AMPA receptor inhibitor, NBQX (30 mg/kg). The neuronal damage assessment, conducted 24 h post-injury, involved a histological analysis, focusing on the factors of neuronal death, oxidative damage, and glial cell activation. The statistical analysis included the performance of an ANOVA followed by a Bonferroni post hoc test, with the data presented as mean ± SEM values and the significance determined at p <
0.05. RESULTS: Treatment with l-theanine was observed to significantly mitigate the zinc accumulation, neuronal death, and cognitive impairments associated with TBI. These benefits are likely attributed to the inhibition of AMPA receptor activity and reduction in neuroinflammation, possibly enhanced as a result of increased glutathione production. CONCLUSION: This study suggests that l-theanine can perform a neuroprotective role in TBI, modulating AMPA receptor activation and diminishing neuroinflammation. Its antioxidant and anti-inflammatory properties further enhance the material's potential use as a therapeutic agent for reducing hippocampal damage caused as a result of a TBI.