目的 基于GSK3β/Nrf2/HO-1 及NF-κB 信号通路探讨青藤碱（Sinomenine，SIN）对帕金森病（Parkinson’s disease，PD）小鼠的干预作用及机制。方法 将C57BL/6 小鼠，随机分为6 组：正常组、模型组、阳性药组 （左旋多巴，75 mg·kg-1）及青藤碱低、中、高剂量组（20、40、80 mg·kg-1），每组8 只。腹腔注射20 mg·kg-1 1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP），每天1 次，共造模5 d。在注射MPTP 后1 h 进行灌胃给药，每 天1 次，共12 d。在给药第11 天对小鼠进行爬杆实验，第12 天进行转棒实验，测试小鼠行为学变化。采用 ELISA 法检测血清肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL-1β）、IL-6 含量；RT-qPCR 法检测脑组织中 TNF-α、IL-1β、IL-6 mRNA 表达水平；Western Blot 法检测脑组织中TH、Nrf2、HO-1、p-GSK3β、GSK3β、 p-IκB、IκB、p-NF-κB、NF-κB 蛋白表达水平。结果 与正常组比较，模型组小鼠的自动转身潜伏期（T-turn） 明显延长（P＜0.05），掉落次数显著增多（P＜0.001）；脑组织中TH 蛋白表达水平显著降低（P＜0.01），IL-1β、 TNF-α、IL-6 mRNA 表达水平显著升高（P＜0.001）；血清TNF-α、IL-1β、IL-6 水平明显升高（P＜0.05，P＜ 0.01）；脑组织中p-GSK3β/GSK3β、Nrf2、HO-1 蛋白表达水平显著降低（P＜0.05，P＜0.001），p-IκB/IκB、 p-NF-κB/NF-κB 蛋白表达比值显著升高（P＜0.001）。与模型组比较，青藤碱中、高剂量组小鼠的T-turn 明显 缩短（P＜0.05，P＜0.001），掉落潜伏期明显延长（P＜0.05，P＜0.01），掉落次数显著减少（P＜0.001），脑组织 中TH 蛋白表达水平显著升高（P＜0.01，P＜0.001），血清TNF-α 水平明显降低（P＜0.05）；各给药组小鼠脑组 织中IL-1β、TNF-α、IL-6 mRNA 表达水平均显著降低（P＜0.001），血清IL-1β、IL-6 水平显著降低（P＜ 0.01，P＜0.001），脑组织中p-GSK3β/GSK3β、Nrf2、HO-1 蛋白表达水平显著升高（P＜0.05，P＜0.01，P＜ 0.001），p-IκB/IκB、p-NF-κB/NF-κB 蛋白表达比值显著降低（P＜0.001）。结论 青藤碱可通过调节帕金森病 小鼠脑内GSK3β /Nrf2/HO-1 和NF-κB 通路，增强抗氧化应激能力和抑制神经炎症，从而发挥神经保护作用。

Abstract: Objective To investigate the intervention effect and mechanism of sinomenine （SIN） on Parkinson’s disease （PD） mice based on GSK3β/Nrf2/HO-1 and NF- κB signaling pathways. Methods C57BL/6 mice were randomly divided into 6 groups：normal group，model group，positive drug group （Levodopa，75 mg‧kg-1） and SIN low-， medium- and high- dose groups （20， 40， 80 mg‧kg-1）， with 8 mice in each group. Mice were intraperitoneally injected with 20 mg‧kg-1 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine （MPTP） once a day for 5 days. Intragastric administration was performed 1 hour after injection of MPTP，once a day for 12 days. On the day 11 of administration， the mice were subjected to a pole-climbing experiment， and on the day 12， a rotating rod experiment was performed to test the behavioral changes of the mice. The levels of serum tumor necrosis factor-α （TNF-α），interleukin-1β （IL-1β） and IL-6 were detected by ELISA. The mRNA expression levels of TNF-α， IL-1β and IL-6 in brain tissue were detected by RT-qPCR. The protein expression levels of TH，Nrf2，HO-1，p- GSK3β， GSK3β， p-IκB， IκB， p-NF-κB and NF-κB in brain tissue were detected by Western Blot. Results Compared with the normal group， the automatic turning latency （T-turn） of the model group was significantly prolonged（P＜0.05），and the number of falls was significantly increased （P＜0.001） . The expression level of TH protein in brain tissue was significantly decreased （P＜0.01），and the mRNA expression levels of IL-1β，TNF-α and IL-6 were significantly increased （P＜0.001） . The serum levels of TNF-α，IL-1β and IL-6 were significantly increased （P＜0.05， P＜0.01） . The protein expression levels of p-GSK3β/GSK3β， Nrf2 and HO-1 in brain tissue were significantly decreased （P＜0.05， P＜0.001）， and the protein expression ratios of p-IκB/IκB and p-NF-κB/NF-κB were significantly increased （P＜0.001） . Compared with the model group， the T-turn in the Sin medium-and high-dose groups was significantly shortened （P＜0.05， P＜0.001）， the falling latency was significantly prolonged （P＜0.05， P＜0.01）， the times of falls was significantly reduced （P＜0.001）， the expression level of TH protein in brain tissue was significantly increased （P＜0.01，P＜0.001），and the level of serum TNF-α was significantly decreased （P＜0.05） . The mRNA expression levels of IL-1β，TNF-α and IL-6 in brain tissue of mice in each administration group were significantly decreased （P＜0.001），the serum levels of IL- 1β and IL-6 were significantly decreased（P＜0.01，P＜0.001），the protein expression levels of p-GSK3β/GSK3β， Nrf2 and HO-1 in brain tissue were significantly increased （P＜0.05， P＜0.01， P＜0.001）， and the protein expression ratios of p-IκB/IκB and p-NF-κB/NF-κB were significantly decreased （P＜0.001） . Conclusion SIN can enhance anti-oxidative stress and inhibit neuroinflammation by regulating GSK3β/Nrf2/HO-1 and NF- κB pathways in the brain of Parkinson’s disease mice，thereby exerting neuroprotective effects.

R285.5

国家自然科学基金项目（81973545）；中药质量研究国家重点实验室（澳门科技大学）开放课题[QRCM（MUST）-2020-2022/2R2102]。