Potential Neuroprotective Effects of Docosahexaenoic Acid on Glutamate-Induced Neurotoxicity: A Systematic Review of Pre-Clinical Studies

Background/Objectives: Excitotoxicity, primarily caused by excessive glutamate signaling, is a significant contributor to the aetiology of several neurological disorders. Docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid, is known for its neuroprotective properties, including antioxidants and anti-inflammatory effects. However, the existing literature has not sufficiently reviewed its specific role in glutamate-induced excitotoxicity. This systematic review aimed to provide comprehensive information from the literature on the neuroprotective effects of DHA in models of glutamate-induced neurotoxicity. Methods: A systematic search was conducted in the Cochrane Library, Scopus, Web of Science, PubMed, ScienceDirect, and Google Scholar, following PRISMA 2020 guidelines. The following keywords were used: DHA OR docosahexaenoic acid AND excitotoxicity OR glutamate-induced excitotoxicity OR glutamate-induced neurotoxicity. A total of 475 articles were screened, and 13 original articles published between 2003 and 2025 were included for data extraction. These studies included nine in vivo animal studies, three ex vivo studies, and one in vitro study. The risk of bias was assessed using SYRCLE’s methodology. Results: Our findings demonstrate that DHA provides substantial neuroprotection against excitotoxicity through antioxidative, anti-inflammatory, and anti-apoptotic mechanisms. Furthermore, DHA enhances neuronal function and cognitive performance by modulating neurotransmitter levels and glutamate-related signaling pathways. Despite these positive outcomes, heterogeneity across studies suggests that the neuroprotective properties of DHA may be affected by various parameters, such as the source of DHA, treatment dose and duration, age and experimental design. Conclusions: Although previous studies have demonstrated the benefits of DHA in preclinical and clinical settings of neurological disorders, further clinical studies focusing on the modulation of excitotoxicity by DHA are needed to validate its translational efficacy and therapeutic significance.