目的 探讨α-香附酮激活小鼠前额叶皮质细胞外调节蛋白激酶（ERK）/核因子红系2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）通路，改善抑郁样小鼠中枢和外周炎症的分子机制。方法 将小鼠随机分为5组：对照组、模型组、氟西汀（10 mg·kg^-1）组和α-香附酮低、高剂量（5、10 mg·kg^-1）组，除对照组外，利用慢性温和不可预知性应激（CUMS）联合孤养建立小鼠抑郁症模型，采用糖水偏好、悬尾（TST）、强迫游泳（FST）、旷场（OFT）、新环境进食抑制（NSFT）实验评估小鼠抑郁样行为；利用激光散斑技术和小动物超声分析血流动力学；酶联免疫吸附测定（ELISA）法检测小鼠血清和前额叶皮质炎症因子水平； Western blotting、免疫荧光、实时荧光定量PCR（qRT-PCR）检测小鼠前额叶皮质ERK/Nrf2/HO-1信号通路表达； qRT-PCR检测抗氧化反应元件（ARE）基因表达。结果 与模型组比较，α-香附酮高剂量组小鼠糖水偏好程度显著提高（P＜0.001），FST（P＜0.05、0.01）和TST（P＜0.05）的不动时间显著缩短，进入OFT中心的次数及在NSFT中摄食潜伏期回调，但均无显著性差异。α-香附酮高剂量组小鼠脑血流量增加（P＜0.01）、脑血管直径增大（P＜0.05），小鼠颈动脉血流速度时间积分（VTI）（P＜0.01）、VTI峰值血流量（P＜0.01）和平均血流速度（P＜0.05）均显著回调； α-香附酮高剂量组小鼠血清中白细胞介素（IL）-6（P＜0.05）、IL-1β（P＜0.05）、活性氧（ROS）（P＜0.01）含量显著降低，IL-10（P＜0.01）水平均显著升高； α-香附酮高剂量组小鼠前额叶皮质中IL-6（P＜0.01）、IL-1β（P＜0.05）含量显著降低，IL-10（P＜0.05）的含量显著升高； α-香附酮高剂量组小鼠前额叶皮质ERK（P＜0.05）、Nrf2（P＜0.05）、HO-1（P＜0.05）的蛋白表达含量均显著升高，ERK（P＜0.05）、Nrf2（P＜0.001）、HO-1（P＜0.001）的荧光表达含量均显著升高； α-香附酮高剂量组小鼠前额叶皮质ERK（P＜0.01）、Nrf2（P＜0.01）、HO-1（P＜0.01）的基因表达均显著升高，ARE（P＜0.05）基因表达显著升高。结论 α-香附酮能有效抑制CUMS小鼠中枢和外周炎性水平，提高抗氧化能力，从而产生抗抑郁效应，其机制可能与激活前额叶皮质ERK/Nrf2/HO-1通路相关。

Objective To investigate the molecular mechanism by which α-cyperone activates the extracellular signal-regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in mouse prefrontal cortex, thereby alleviating central and peripheral inflammation in depression-like mice. Methods Mice were randomly divided into five groups: control group, model group, fluoxetine (10 mg·kg^-1) group, and low- and high-dose α-cyperone groups (5 and 10 mg·kg^-1). Except for the control group, depression models were established using chronic unpredictable mild stress (CUMS) combined with social isolation. Depression-like behaviors were assessed using sucrose preference test, tail suspension test (TST), forced swimming test (FST), open field test (OFT), and novelty-suppressed feeding test (NSFT). Laser speckle contrast imaging and small animal ultrasound were used to analyze hemodynamics. Serum and prefrontal cortex inflammatory levels were measured by enzyme-linked immunosorbent assay (ELISA). Western blotting, immunofluorescence, and real-time quantitative PCR (qRT-PCR) were employed to detect expression of the ERK/Nrf2/HO-1 signaling pathway in the prefrontal cortex; qRT-PCR was also used to assess antioxidant response element (ARE) gene expression. Results Compared with the model group, the high-dose α-cyperone group showed significantly increased sucrose preference (P < 0.001), significantly reduced immobility time in FST (P < 0.05, 0.01) and TST (P < 0.05), and improved center entries in OFT and feeding latency in NSFT, although the latter two changes were not statistically significant. The high-dose α-cyperone group exhibited increased cerebral blood flow (P < 0.01) and larger cerebral vascular diameter (P < 0.05); carotid artery velocity-time integral (VTI) (P < 0.01), peak VTI blood flow (P < 0.01), and mean blood flow velocity (P < 0.05) were all significantly improved. Serum levels of interleukin (IL)-6 (P < 0.05), IL-1β (P < 0.05), and reactive oxygen species (ROS) (P < 0.01) were significantly decreased, while IL-10 levels were significantly elevated (P < 0.01). In the prefrontal cortex, IL-6 (P < 0.01) and IL-1β (P < 0.05) levels were significantly reduced, whereas IL-10 levels were significantly increased (P < 0.05). Protein expression of ERK (P < 0.05), Nrf2 (P < 0.05), and HO-1 (P < 0.05) was significantly upregulated, as was fluorescent expression of ERK (P < 0.05), Nrf2 (P < 0.001), and HO- 1 (P < 0.001). Gene expression of ERK (P < 0.01), Nrf2 (P < 0.01), HO-1 (P < 0.01), and ARE (P < 0.05) in the prefrontal cortex was significantly enhanced. Conclusion α-Cy can effectively inhibit the central and peripheral inflammatory levels of CUMS mice, improve antioxidant capacity and thus produce antidepressant effects, and the mechanism may be related to the activation of the ERK/Nrf2/HO-1 pathway in the prefrontal cortex by α-Cy.

R965

国家自然科学基金资助项目（82560875）；江西省自然科学基金资助项目（20232ACB206052）；江西省自然科学基金面上项目（20232BAB206175）