Chijioke_2026_Biogerontology_27_

Accelerated cellular perturbations such as cellular senescence, neuroinflammation and oxidative stress are hallmarks of Alzheimer's disease, a neurodegenerative disease associated with memory decline. However, the senolytic effects of silymarin, a flavonolignan with known antioxidant and anti-inflammatory properties, on memory decline remain unknown. Hence, we investigated the effect of silymarin on doxycycline-mediated senescence and exacerbated neuroinflammation in lipopolysaccharide-induced memory-impaired mice. Five groups of adult Swiss female mice (n = 10) were exposed to doxycycline-induced accelerated senescence for 21 days, followed by lipopolysaccharide-induced neuroinflammation from days 15-21, and silymarin (50 and 100 mg/kg, p.o.) or donepezil (1 mg/kg, p.o.) treatments. Spatial and non-spatial memory, and social and motor function tests in mice were assessed. Biochemical assays were performed on the prefrontal cortex and hippocampus to assess senescence-associated secretory phenotypes (SASPs), including SA-beta-galactosidase activity, cytokines (TNF-alpha, IL-6, IL-10), amyloid-beta levels, acetylcholinesterase activity, oxidative stress markers, and molybdoenzymes. Doxycycline-lipopolysaccharide-exacerbated memory impairments were reversed by silymarin, accompanied by reduced molybdoenzymes, malondialdehyde, nitrite, and elevated antioxidants (glutathione, superoxide-dismutase, catalase) in the prefrontal cortex and hippocampus. Additionally, silymarin reverses doxycycline-exacerbated lipopolysaccharide-induced increases in IL-6 and TNF-alpha release and myeloperoxidase activity while also reducing IL-10 levels. Similar to donepezil, silymarin reduced heightened acetylcholinesterase activity associated with doxycycline-enhanced lipopolysaccharide-induced accumulation of cortical SA-beta-galactosidase and amyloid-beta levels, relative to the doxycycline-lipopolysaccharide group. These findings suggest that silymarin ameliorates doxycycline-lipopolysaccharide-exacerbated memory impairment and modulates senescence and neuroinflammation by reducing oxidative stress, SASP marker levels, and amyloid-beta concentrations in the prefrontal cortex and hippocampus of mouse brains.