Resveratrol as a potential natural compound to ameliorate cognitive impairment in aluminum-exposed mice: impacts on behavior, purinergic system, and brain inflammation.

UNLABELLED: Aluminum (Al³⁺) accumulates in the brain and has been linked to neurodegeneration. When combined with citrate, its absorption increase, raising the risk of neurodegenerative disorders such as Alzheimer’s disease. Resveratrol (RSV), a polyphenol with anti-inflammatory, antioxidant, and neuroprotective properties, has been associated with aging prevention by reducing oxidative stress. This in vivo study aimed to determine whether RSV could protect male Swiss mice from Al³⁺-induced cognitive impairment, alterations in purinergic signaling, and brain inflammation. The study was conducted using 60 animals treated with aluminum chloride (AlCl₃ 50 mg/Kg, gavage), citrate (AlCl₃ 50 mg/Kg + CIT 100 mg/Kg, gavage), and resveratrol (AlCl₃ 50 mg/Kg + RSV 100 mg/Kg, gavage), along with their respective Controls, for 30 days every 48 h. Behavioral assessments included the open field test, object recognition test, and Y-maze test to evaluate cognitive performance. Enzymatic activity of purinergic pathways and levels of receptors and inflammation-related molecules were also analyzed. AlCl₃ and AlCl₃ + CIT induced an inflammatory response in mice, as evidenced by the modulation of purinergic system enzymes associated with inflammation. Al³⁺ intoxication also triggered behavior alterations, which was modulated by CIT and alleviated by RSV treatment. Western blot findings revealed that AlCl₃ and AlCl₃ + CIT altered protein levels of purinergic receptors (A1R, A2AR, and P2 × 7R), the inflammasome protein NLRP3, the pro-inflammatory cytokine IL-1β, and the neurotrophic factor BDNF. RSV counteracted the toxic effects of Al³⁺, providing neuroprotection against its toxicity and presenting itself as a potential therapeutic candidate for cognitive deficits. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-026-01859-z. UNLABELLED: RSV counteracts Al3+-induced effects in purinergic enzymes and receptors of the cerebral cortex. The addition of citrate altered the toxicity of Al³⁺. RSV has neuroprotective effects against Al3+-induced toxicity. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-026-01859-z.