Hesperidin attenuates aluminum chloride-induced cognitive impairment by modulating ERK/MAPK Signaling, tau protein immunoexpression, neuroinflammation, and microglial activation in mice.

Aluminum chloride (AlCl₃) is widely used to model Alzheimer's-related neurotoxicity and cognitive decline. Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory properties, has unclear neuroprotective mechanisms against aluminum-induced neurodegeneration. This study investigated hesperidin's neuroprotective effects against AlCl₃-induced cognitive impairment in mice, focusing on ERK/MAPK signaling, tau expression, neuroinflammation, and microglial activation. Mice received AlCl₃ (100 mg/kg) daily for four weeks, hesperidin (100 mg/kg), both, or vehicle, with hesperidin administered during weeks 3 and 4 in the co-treated group. Cognitive function was assessed using the Morris water maze and Y-maze tests. TNF-α and IL-1β were quantified in brain tissue. IBA1-positive microglial density, ERK immunoreactivity, and tau expression were evaluated immunohistochemically in the hippocampal CA3 region and the prefrontal cortex. AlCl₃ impaired spatial and working memory, elevated pro-inflammatory cytokines, increased microglial activation, and upregulated ERK and tau immunoexpression in both regions. Hesperidin co-treatment significantly rescued cognitive deficits, attenuated neuroinflammation, reduced microglial reactivity, modulated ERK signaling, and decreased tau overexpression. These findings demonstrate that hesperidin protects against AlCl₃-induced neurodegeneration by concurrently modulating neuroinflammatory and kinase-dependent pathways, supporting its therapeutic potential in aluminum-related tauopathies.