Ginsenoside Rg1 Restores Sirt2/Foxo1 Expression and Alleviates Autism-Like Behaviors in a Valproic Acid Induced Male Mouse Model.

Abstract

This study investigated whether Ginsenoside Rg1 (Rg1) alleviates autism-like behaviors in mice prenatally exposed to valproic acid (VPA) via Sirt2/Foxo1 signaling. Pregnant C57BL/6J mice received a single intraperitoneal injection of VPA (600 mg/kg) on embryonic Day 12.5 to establish an autism model. At 8 weeks of age, male offspring were randomly divided into four groups: Normal, VPA, VPA + Rg1 (5 mg/kg), and VPA + Rg1 (10 mg/kg). Rg1 was administered once daily for 28 days. Behavioral assessments included grooming, rearing, locomotor activity, social interaction, novel object recognition, open field, and marble-burying tests. Molecular assays measured Sirt2/Foxo1 expression, inflammatory cytokines, oxidative stress markers in the hippocampus and prefrontal cortex. Nissl staining was performed to evaluate neuronal integrity in the prefrontal cortex and hippocampus. Rg1 administration significantly ameliorated core autism-like behaviors in VPA-exposed mice, including deficits in social interaction, recognition memory, and anxiety- and compulsive-like behaviors, as well as excessive grooming and marble-burying. VPA reduced Sirt2/Foxo1 expression, increased levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) activity in both brain regions. Rg1 treatment reversed these alterations in a dose-responsive manner, with the 10 mg/kg dose yielding more pronounced behavioral and molecular improvements than the 5 mg/kg dose. Nissl staining revealed significant neuronal loss in VPA-exposed mice, which was partially restored by Rg1 treatment. These findings suggest that Rg1 alleviates VPA-induced behavioral and neuropathological abnormalities, potentially via Sirt2/Foxo1-mediated regulation of neuroinflammation and oxidative stress, and may represent a promising therapeutic strategy for autism spectrum disorder.