Severe neurotoxicity induced by the combined exposure to cadmium and high-fat diet: Protective role of naringin against oxidative, mitochondrial, and inflammatory brain damage

Environmental cadmium (Cd) contamination has increased in recent years, coinciding with the expansion of industrial activities and the global consumption of high-fat diets (HFD). Both are recognized as independent risk factors for neurodegenerative processes, yet their combined effects on brain function remain poorly characterized. This study is the first to investigate the interactive neurotoxicity of chronic Cd exposure and HFD, and to assess the potential protective effects of naringin, a flavonoid with known antioxidant and anti-inflammatory properties. Eighty female NMRI mice were assigned to eight groups receiving low- or high-fat diets, with or without Cd (0.5 or 5 ppm) in drinking water for 12 weeks. Two groups co-exposed to Cd and HFD received naringin (50 or 100 mg/kg). Behavioral assessments (Y-maze, shuttle box) were conducted, along with evaluations of oxidative stress markers, mitochondrial function, acetylcholinesterase activity, DNA fragmentation, histopathology, and proinflammatory cytokines. Cd and HFD individually induced cognitive deficits, oxidative imbalance, mitochondrial dysfunction, inflammation, and cholinergic disruption, which were more pronounced when both insults were combined. Naringin, particularly at a dose of 100 mg/kg, effectively reversed these alterations, restoring redox homeostasis and neuronal integrity without reducing Cadmium accumulation in brain tissue. These findings demonstrate, for the first time, that naringin mitigates the synergistic neurotoxic effects of Cd and HFD, highlighting its therapeutic potential against modern environmental and dietary challenges.