Abstract
Monosodium glutamate (MSG)-induced excitotoxicity is a major factor contributing to cognitive decline and neurodegeneration. Given the well-established roles of vitamin D (Vit D) and omega-3 polyunsaturated fatty acids (N-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in neuroprotection, the present study aimed at analyzing their possible neuroprotective efficacy against MSG-induced neurotoxicity in rats, concerning the behavioral performance, hippocampal histological integrity, and pathological protein accumulation, along with determination of the inflammatory marker levels and mRNA expression of vitamin D receptors (VDR) and other neurodegeneration-related genes. Fifty male Sprague Dawley rats were randomly allocated to a control, an MSG, and three treatment groups that received MSG and either Vit D or N-3 PUFA supplements in combinations or alone for 4 weeks. At the end of the study, five behavioral tests were conducted to assess cognitive functions, motor activity, and anxiety-related behaviors, and hippocampal tissues were analyzed for tau pathology, neuroinflammation, expression of VDR, and neurodegeneration-related markers. The results demonstrated that supplementation with Vit D (1 mcg/kg) and N-3 PUFAs (300 mg/kg EPA + DHA) profoundly attenuated MSG-induced neurodegeneration. The combined therapy decreased neuronal damage caused by MSG by 87% and tau pathology by 83%. The combined treatment further suppressed pro-inflammatory cytokines (TNF-α: 52%; IL-6: 65%) and elevated anti-inflammatory IL-10 by 2.8-fold, demonstrating a dual anti-inflammatory action. A major upregulation of hippocampal VDR by 4.6-fold was noted, with stabilization of calcium homeostasis and normalization of caspase-3 and α-synuclein expression. Our findings confirm that Vit D and N-3 PUFAs exhibit substantial synergistic neuroprotective abilities that might be mediated through synergistic VDR upregulation, providing a promising dietary intervention against MSG-induced excitotoxicity and highlighting their broader implications for supporting cognitive health and mitigating the adverse effects of other neurotoxins.