目的研究二仙汤对围绝经期抑郁症（PMD）模型大鼠行为学、性激素水平、相关基因表达及血清代谢谱的影响，探讨其潜在作用机制。方法采用双侧卵巢摘除（OVX）联合42 d慢性不可预知温和刺激（CUMS）建立PMD模型。设置对照组（不造模）、模型组、氟哌噻吨美利曲辛（FM，阳性对照，2.2 mg·kg^-1）组、雌二醇（E₂，阳性对照，0.1 mg·kg^-1）组及二仙汤高、中、低剂量（9.6、4.8、2.4 g·kg^-1）组，实验后21 d每天给药1次。通过阴道涂片、体质量和摄食量测定、蔗糖水偏好实验（SPT）、强迫游泳实验（FST）及Morris水迷宫实验（MWM）评价模型及行为学变化；采用苏木素-伊红（HE）染色观察海马组织病理形态改变；利用酶联免疫吸附测定法（ELISA）检测血清E₂、促黄体生成素（LH）、促卵泡生成素（FSH）水平；通过实时荧光定量PCR（qRT-PCR）技术检测海马组织中5-羟色胺1A受体基因（Htr1a）、脑源性神经营养因子（BDNF）、原肌球蛋白受体激酶B（TrkB）及子宫组织中的雌激素受体1（Esr1）和Esr2 mRNA表达。根据药效学结果，选取对照组、模型组和二仙汤高剂量组进行UPLC-Q-TOF/MS血清非靶向代谢组学分析。结果与模型组比较，二仙汤各剂量组大鼠体质量、体质量增长率，摄食量均显著降低（P＜0.05、0.01）；二仙汤高剂量组大鼠糖水偏好率升高（P＜0.01），不动时间和逃避潜伏期缩短（P＜ 0.01），目标象限停留时间显著增加（P＜0.01）；二仙汤各剂量组海马区病理损伤均有不同程度改善，其中高剂量组神经元排列和细胞形态改善最明显；二仙汤高、中剂量可升高E₂水平并降低LH和FSH水平（P＜0.01）；二仙汤各剂量组海马组织Htr1a、BDNF及TrkB mRNA表达显著下降，子宫组织Esr1和Esr2 mRNA表达亦显著下调（P＜0.05、0.01）；代谢组学结果显示，二仙汤高剂量组可使模型大鼠血清代谢轮廓向对照组回归，共回调37种异常血清代谢物，主要涉及牛磺酸、L-苯丙氨酸、亚油酸、磷脂酰乙醇胺及多种磷脂酰胆碱等；通路富集主要涉及亚油酸代谢、α-亚麻酸代谢、牛磺酸和亚牛磺酸代谢及甘油磷脂代谢。结论二仙汤可改善PMD模型大鼠抑郁样行为、认知功能障碍和海马病理损伤，其机制可能与调节下丘脑-垂体-卵巢轴（HPO）轴功能、增强雌激素受体表达、激活5-羟色胺（5-HT）1A/BDNF/TrkB相关信号，并重塑脂质及牛磺酸相关代谢稳态有关。

Objective To investigate the effects of Erxian Decoction (EXD) on behavior, sex hormone levels, related gene expression, and serum metabolic profiles in a rat model of perimenopausal depression (PMD), and to explore its potential mechanisms. Methods A PMD rat model was established by bilateral ovariectomy (OVX)combined with 42 days of chronic unpredictable mild stress (CUMS). Female SD rats were control group (without modeling), the model group, the flupentixol-melitracen (FM, positive control, 2.2 mg·kg^-1) group, the estradiol (E₂, positive control, 0.1 mg·kg^-1) group, and the high, medium and low doses of EXD (9.6, 4.8, 2.4 g·kg^-1) groups. The drug was administered once a day every 21 d after the experiment. Behavioral changes were evaluated by the sucrose preference test (SPT), forced swimming test (FST), and Morris water maze (MWM). Hippocampal pathology was observed by HE staining. Serum estradiol (E₂), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured by ELISA. The mRNA levels of hippocampal serotonin 1A receptor gene (Htr1a), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and uterine Esr1, Esr2 were detected by qRT-PCR. Based on pharmacodynamic results, serum samples from the control, model, and high-dose EXD groups were analyzed by UPLC-Q-TOF/MS-based untargeted metabolomics. Results Compared with the model group, rats in all dosage groups of Erxian Decoction showed significantly reduced body weight, body weight gain rate, and food intake (P < 0.05, 0.01). The high-dose group exhibited increased sucrose preference (P < 0.01), shortened immobility time and escape latency (P < 0.01), and significantly prolonged time spent in the target quadrant (P < 0.01). Pathological damage in the hippocampus was improved to varying degrees across all dosage groups, with the most notable improvement observed in neuronal alignment and cell morphology in the high-dose group. High and medium doses of Erxian Decoction elevated E₂ levels while reducing LH and FSH levels (P < 0.01). Expression of Htr1a, BDNF, and TrkB mRNA in hippocampal tissue, as well as Esr1 and Esr2 mRNA expression in uterine tissue, were significantly downregulated in all dosage groups (P < 0.05, 0.01). Metabolomics analysis revealed that the high-dose group restored the serum metabolic profile of model rats toward that of the control group, correcting 37 abnormal serum metabolites, primarily including taurine, L-phenylalanine, linoleic acid, phosphatidylethanolamine, and various phosphatidylcholines. Pathway enrichment analysis mainly involved linoleic acid metabolism, alpha-linolenic acid metabolism, taurine and hypotaurine metabolism, and glycerophospholipid metabolism. Conclusion Erxian Decoction improves depression-like behavior, cognitive dysfunction, and hippocampal injury in PMD rats, possibly by regulating the HPO axis, enhancing estrogen receptor expression, activating 5-HT1A/BDNF/TrkB signaling, and restoring lipid and taurine-related metabolic homeostasis.

R965

黑龙江中医药大学校基金青年创新项目（14011250019）