目的 探究川芎油经鼻吸入给药后对慢性不可预知温和应激（chronic unpredictable mild stress，CUMS）抑郁小鼠的影响及作用机制。方法 通过气相色谱-质谱（gas chromatography-mass spectrometry，GC-MS）鉴定川芎油主要成分；构建小鼠CUMS抑郁模型，给予药物干预后，采用行为学实验、苏木素-伊红（hematoxylin-eosin，HE）及尼氏染色评价川芎油的药效作用；采用ELISA、Western blotting、qRT-PCR及16S rRNA进行机制研究。结果 通过GC-MS鉴定川芎油的主要成分为Z-藁本内酯和洋川芎内酯A。经鼻吸入川芎油能显著改善CUMS小鼠的抑郁样行为（P＜0.05、0.01），减轻海马神经元损伤，上调海马组织脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）/原肌球蛋白受体激酶B（tyrosine receptor kinase B，TrkB）/环磷腺苷效应元件结合蛋白（cAMP-response element binding protein，CREB）信号通路相关蛋白表达（P＜0.05、0.01），升高5-羟色胺（5-hydroxytryptamine，5-HT）、去甲肾上腺素（norepinephrine，NE）等单胺类神经递质水平（P＜0.05、0.01），抑制下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal，HPA）轴的亢进（P＜0.05、0.01），抑制结肠组织中肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）等促炎因子水平（P＜0.05、0.01），增强屏障功能（P＜0.05、0.01），显著改善CUMS诱导的肠道微生物失调。CREB特异性抑制剂666-15显著逆转川芎油的抗抑郁作用（P＜0.01）。结论 经鼻吸入川芎油通过BDNF/TrkB/CREB通路改善肠道功能障碍，从而治疗抑郁。

Objective To investigate the effect and mechanism of Chuanxiong (Chuanxiong Rhizoma) oil inhalation via nasal administration on chronic unpredictable mild stress (CUMS)-induced depressive mice. Methods The main components of Chuanxiong Rhizoma oil were identified by gas chromatography-mass spectrometry (GC-MS). A CUMS-induced depressive mouse model was established, and after drug intervention, the pharmacological effects of Chuanxiong Rhizoma oil were evaluated through behavioral tests, hematoxylin-eosin (HE) staining and Nissl staining. Mechanistic studies were conducted using ELISA, Western blotting, qRT-PCR and 16S rRNA. Results GC-MS identified Z-ligustilide and senkyunolide A as the primary components of Chuanxiong Rhizoma oil. Nasal inhalation of Chuanxiong Rhizoma oil significantly alleviated depressive-like behaviors in CUMS mice (P < 0.05, 0.01), reduced hippocampal neuronal damage, upregulated the expressions of brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB)/cAMP-response element binding protein (CREB) signaling pathway related proteins in hippocampus (P < 0.05, 0.01), elevated levels of monoamine neurotransmitters such as 5-hydroxytryptamine (5-HT) and norepinephrine (NE) (P < 0.05, 0.01), inhibited the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis (P < 0.05, 0.01), suppressed pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) in colon tissue (P < 0.05, 0.01), enhanced barrier function (P < 0.05, 0.01), and significantly ameliorated CUMS-induced gut microbiota dysbiosis. The CREB-specific inhibitor 666-15 significantly reversed the antidepressant effects of Chuanxiong Rhizoma oil (P < 0.01). Conclusion Nasal inhalation of Chuanxiong Rhizoma oil alleviates depression by improving gut dysfunction through BDNF/TrkB/CREB pathway.

R285.5

国家自然科学基金资助项目（82474220）；成都中医药大学“杏林学者”学科人才科研提升计划（QJJJ2022014）；四川省中医药科技产业创新团队专项（2022C005）