Song Fan-Xu, Wu Qing-Wei, Pan Wei, Liu Li-Jun, Li Xin, Zhou Xue, Yu Zong-Yao, Ning Xin, Guo Lan-Min
Pediatric Health Department, Rehabilitation Medicine College, Jiamusi University; Jiamusi University Affiliated Third Hospital; Heilongjiang Province Key Laboratory of Children's Neurorehabilitation, Jiamusi, Heilongjiang, China.
Traditional Rehabilitation Department, Rehabilitation Medicine College, Jiamusi University; Jiamusi University Affiliated Third Hospital; Heilongjiang Province Key Laboratory of Children's Neurorehabilitation, Jiamusi, Heilongjiang, China.
Kaohsiung J Med Sci. 2025 Jul 7:e70078. doi: 10.1002/kjm2.70078.
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.
本研究调查了人参皂苷Rg1（Rg1）是否通过Sirt2/Foxo1信号通路减轻产前暴露于丙戊酸（VPA）的小鼠的自闭症样行为。怀孕的C57BL/6J小鼠在胚胎第12.5天接受一次腹腔注射VPA（600mg/kg）以建立自闭症模型。在8周龄时，将雄性后代随机分为四组：正常组、VPA组、VPA + Rg1（5mg/kg）组和VPA + Rg1（10mg/kg）组。Rg1每天给药一次，持续28天。行为评估包括梳理、竖毛、运动活动、社交互动、新物体识别、旷场和埋珠试验。分子检测测量海马体和前额叶皮质中的Sirt2/Foxo1表达、炎性细胞因子、氧化应激标志物。进行尼氏染色以评估前额叶皮质和海马体中的神经元完整性。给予Rg1可显著改善VPA暴露小鼠的核心自闭症样行为，包括社交互动缺陷、识别记忆缺陷以及焦虑样和强迫样行为，以及过度梳理和埋珠行为。VPA降低了Sirt2/Foxo1表达，增加了两个脑区中白细胞介素（IL）-1β、IL-6、肿瘤坏死因子-α（TNF-α）和丙二醛（MDA）的水平，并降低了超氧化物歧化酶（SOD）活性。Rg1治疗以剂量反应方式逆转了这些改变，10mg/kg剂量比5mg/kg剂量产生更明显的行为和分子改善。尼氏染色显示VPA暴露小鼠存在明显的神经元丢失，而Rg1治疗可部分恢复。这些发现表明，Rg1可能通过Sirt2/Foxo1介导的神经炎症和氧化应激调节减轻VPA诱导的行为和神经病理异常，可能是自闭症谱系障碍的一种有前景的治疗策略。
