Neuroprotective effects of Ershiwuwei Shanhu pills on APP/PS1 mice through antioxidant enhancement, anti-apoptosis, and MAPK pathway regulation.

Objectives: Alzheimer's disease (AD) involves cognitive impairment, neuronal degeneration, oxidative imbalance, and abnormal MAPK signaling. This study investigated the protective effects of Ershiwuwei Shanhu Pills (ESP) on cognition, oxidative stress, neuronal apoptosis, and MAPK pathway regulation in APP/PS1 mice. Methods: Sixty mice were used, including 50 APP/PS1 transgenic mice randomly assigned to five groups: untreated AD model, donepezil (0.5 mg/kg), and low- (100 mg/kg), medium- (200 mg/kg), or high-dose (400 mg/kg) ESP. Ten wild-type C57BL/6J mice served as normal controls. All treatments were administered orally for 60 days. Cognitive performance was assessed by the Morris water maze. Hippocampal pathology and apoptosis were evaluated by histology and TUNEL staining, while oxidative stress markers, AD-related proteins, and MAPK phosphorylation were measured via ELISA and Western blot. Results: ESP treatment improved learning and memory performance, reduced hippocampal neuronal damage, and decreased neuronal apoptosis. Antioxidant enzyme activities (SOD, CAT, GSH, GSH-PX) increased, whereas MDA and GSSG levels decreased. Circulating Aβ1-40, Aβ1-42, TAU181, and γ-secretase levels were reduced. ESP also downregulated phosphorylation of JNK, ERK, and p38. The medium-dose group showed therapeutic effects comparable to donepezil. Conclusions: ESP exerts neuroprotective effects in APP/PS1 mice by alleviating oxidative stress, inhibiting neuronal apoptosis, and modulating MAPK signaling. These findings suggest ESP as a promising multi-target therapeutic strategy for AD.