Wang Haoran, Zhang Mengyuan, Yang Sen, Jiang Yi, Wu Lijie, Sun Caihong
Department of Children's and Adolescent Health, Public Health College, Harbin Medical University, Harbin, China.
Heilongjiang Province Key Laboratory of Child Development and Genetic Research, Harbin Medical University, Harbin, China.
CNS Neurosci Ther. 2025 Aug;31(8):e70591. doi: 10.1111/cns.70591.
Emerging evidence suggests lipid metabolism dysregulation contributes to autism spectrum disorders (ASD), with the endocannabinoid system (cannabinoid receptors CB1R/CB2R) implicated in lipid homeostasis. This study investigated whether CB1R/CB2R activation improves hippocampal lipid metabolism and ASD-like behaviors in a valproic acid (VPA)-induced ASD rat model.
Male offspring from dams exposed to VPA (600 mg/kg, i.p.) received the CB1R agonist ACPA (0.1 mg/kg) or the CB2R agonist AM1241 (3 mg/kg) from postnatal days 21-27. ASD-like behaviors (marble burying, self-grooming, social interaction, open-field tests) and hippocampal lipid profiles (UPLC-MS/MS) were analyzed.
VPA-exposed rats displayed heightened repetitive behaviors, social deficits, and hyperactivity, all significantly alleviated by ACPA and AM1241. Lipidomics revealed marked reductions in hippocampal phosphatidylcholines, lysophosphatidylcholines, fatty acids, sphingomyelins, ceramides, and phosphatidylethanolamines in VPA rats. Both agonists restored lipid levels to near normal, comparable to controls.
CB1R/CB2R activation ameliorates behavioral abnormalities and rectifies hippocampal lipid dysregulation in VPA-induced ASD models, highlighting cannabinoid receptors as potential therapeutic targets for ASD-associated metabolic disturbances.
新出现的证据表明脂质代谢失调与自闭症谱系障碍（ASD）有关，内源性大麻素系统（大麻素受体CB1R/CB2R）参与脂质稳态。本研究调查了在丙戊酸（VPA）诱导的ASD大鼠模型中，CB1R/CB2R激活是否能改善海马脂质代谢和ASD样行为。
暴露于VPA（600mg/kg，腹腔注射）的母鼠所产雄性后代在出生后第21至27天接受CB1R激动剂ACPA（0.1mg/kg）或CB2R激动剂AM1241（3mg/kg）。分析ASD样行为（大理石掩埋、自我梳理、社交互动、旷场试验）和海马脂质谱（超高效液相色谱-串联质谱法）。
暴露于VPA的大鼠表现出重复行为增加、社交缺陷和多动，ACPA和AM1241均显著缓解了这些症状。脂质组学显示，VPA大鼠海马中的磷脂酰胆碱、溶血磷脂酰胆碱、脂肪酸、鞘磷脂、神经酰胺和磷脂酰乙醇胺显著减少。两种激动剂均将脂质水平恢复至接近正常，与对照组相当。
CB1R/CB2R激活可改善VPA诱导的ASD模型中的行为异常，并纠正海马脂质失调，突出大麻素受体作为ASD相关代谢紊乱潜在治疗靶点的作用。
