Vitexin Protects Against Scopolamine-Induced Cognitive Impairment by Preserving Synaptic Integrity and Modulating Nrf2/HO-1 and NF-κB Signaling Pathways

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Alzheimer's disease is characterized by progressive cognitive decline driven by oxidative stress, neuroinflammation, and synaptic dysfunction. This study investigated the neuroprotective effects of vitexin in a scopolamine (Sco)-induced rat model of cognitive impairment. Forty-two male Wistar rats were randomly assigned to six groups (n = 7 per group): saline, Sco (2 mg/kg/day, i.p.), Sco + vitexin (30 mg/kg/day, oral), Sco + donepezil (1.5 mg/kg/day, i.p.), vitexin alone, and donepezil alone. All treatments were administered for 14 consecutive days. Behavioral assessments using the morris water maze and elevated plus maze revealed that Sco significantly impaired spatial learning and memory while increasing anxiety-like behaviors. Vitexin treatment markedly improved these deficits, with efficacy comparable to donepezil. Biochemically, Sco elevated acetylcholinesterase activity, lipid peroxidation, and oxidative/nitrosative stress markers (TOS, OSI, MDA, Peroxynitrite, NO, and NOS) while decreasing total antioxidant status (TAS). Vitexin reversed these changes. Western blot and immunofluorescence analyses demonstrated that Sco reduced hippocampal BDNF, GDNF, PSD95, and synaptophysin levels and increased GFAP, IL-6, TNF-α, NF-κB p65, and COX-2 expression. Vitexin restored neurotrophic and synaptic proteins, suppressed astrocyte activation and inflammatory signaling, and activated the Nrf2/HO-1 pathway. These findings were further supported by qRT-PCR analysis of BDNF, GDNF, GPX4, and NF-κB. In conclusion, vitexin exerts significant neuroprotective and synaptoprotective effects against Sco-induced cognitive impairment by simultaneously restoring redox balance, suppressing neuroinflammation, and preserving synaptic integrity. These results position vitexin as a promising therapeutic candidate for neurodegenerative disorders, including Alzheimer's disease.