参葛补肾胶囊的多靶点抗抑郁机制研究

Multi-target antidepressant mechanism of Shenge Bushen Capsules

摘要

目的: 系统探究参葛补肾胶囊的多靶点抗抑郁作用机制,重点评估其对多巴胺(dopamine,DA)、去甲肾上腺素(norepinephrine,NE)系统的直接影响以及对脑单胺氧化酶A(monoamine oxidase A,MAO-A)活性的抑制和对缺糖缺氧神经元的保护作用。方法: 采用阿扑吗啡诱导的小鼠刻板行为模型和育亨宾增强毒性实验分别评价其对DA和NE系统的作用;通过体外荧光测定法研究其对小鼠脑MAO-A活性的影响;利用原代培养小鼠皮层神经元建立缺糖缺氧损伤模型,通过检测乳酸脱氢酶(lactate dehydrogenase,LDH)逸漏率评估其神经保护活性。结果: 参葛补肾胶囊对阿扑吗啡诱导的小鼠刻板行为无显著影响,且不增强育亨宾的致死毒性。体外实验表明,该药在4×10^-4 g·mL^－1浓度下对MAO-A具有显著抑制作用。在神经保护实验中,参葛补肾胶囊在10×10^-6 g·mL^－1的低浓度下即能显著降低缺糖缺氧神经元的LDH逸漏率,并呈浓度依赖性。结论: 参葛补肾胶囊的抗抑郁作用并非通过直接调控DA或NE系统实现,其机制与抑制MAO-A活性以减少单胺类神经递质降解以及直接保护神经元免受损伤等多靶点协同作用有关。

Abstract

Objective: To systematically explore the antidepressant multi-target mechanism of Shenge Bushen Capsules, and evaluate its direct effect on dopamine (DA) and norepinephrine (NE) system, as well as the inhibition of monoamine oxidase A (MAO-A) activity and the protective effect on glucose-deficient and hypoxic neurons. Methods: The effects of yohimbine on DA and NE systems were evaluated by apomorphine-induced mouse stereotyped behavior model and yohimbine-enhanced toxicity test, respectively. Its effect on MAO-A activity in mouse brain was studied by in vitro fluorescence assay. The model of oxygen-glucose deprivation injury was established by primary cultured mouse cortical neurons, and the neuroprotective activity was evaluated by detecting the leakage rate of lactate dehydrogenase (LDH). Results: Shenge Bushen Capsules had no significant effect on apomorphine-induced stereotyped behavior and did not enhance the lethal toxicity of yohimbine. In vitro experiments showed that the drug had a significant inhibitory effect on MAO-A at a concentration of 4×10^-4 g·mL^－1. In the neuroprotective experiment, Shenge Bushen Capsules could significantly reduce the LDH leakage rate of glucose-deficient hypoxic neurons at a low concentration of 10×10^-6 g·mL^－1 in a concentration-dependent manner. Conclusion: The antidepressant effect of Shenge Bushen Capsules is not achieved by directly regulating the DA or NE system. The mechanism is related to the inhibition of MAO-A activity to reduce the degradation of monoamine neurotransmitters and the direct protection of neurons from damage.

关键词

参葛补肾胶囊 / 抗抑郁机制 / 单胺氧化酶A / 神经保护 / 多巴胺系统 / 去甲肾上腺素系统

Key words

Shenge Bushen Capsules / antidepressant mechanism / monoamine oxidase A / neuroprotection / dopamine system / norepinephrine system

[1] 谢丽颖. 抑郁症诊断方法与相关干预研究综述[J]. 社会科学前沿, 2024, 13(1): 1-7.
[2] 朱紫青. 抑郁障碍诊疗关键[M]. 南京: 江苏科学技术出版社, 2003: 89-149.
[3] 秦娟娟, 刘振华, 梁艳, 等. 5-羟色胺及其受体与抑郁症[J]. 国际药学研究杂志, 2012, 39(5): 409-413.
[4] 张陈平, 张翔. 抗抑郁药物的现状与新靶点的探索[J]. 药物化学, 2025, 13(2): 194-209.
[5] 黄良峰, 陈洋洋, 赵炳功, 等. 抑郁症的成因及其新药治疗研究进展[J]. 现代生物医学进展, 2018, 18(1): 180-185.
[6] 张海珊, 董惠娟, 扎克亚古丽·吾加买提, 等. 抗抑郁药参葛补肾胶囊的作用机制及临床应用研究进展[J]. 中国新药杂志, 2026, 35(10): 1040-1045.
[7] 陈晶, 刘瑾春, 张鹏杰, 等. 维生素B₁₂对抑郁大鼠行为学和脑单胺类神经递质及脑源性神经营养因子的影响[J]. 四川大学学报(医学版), 2025, 56(1): 206-214.
[8] 李成功, 胡时先, 任宾, 等. HPLC-一测多评法测定参葛补肾胶囊中总黄酮醇苷的含量[J]. 中国药物评价, 2024, 41(3): 198-203.
[9] KOCH S, PERRY KW, NELSON DL, et al. R-fluoxetine increases extracellular DA, NE, as well As₅-HT in rat prefrontal cortex and hypothalamus an in vivo microdialysis and receptor binding study[J]. Neuropsychopharmacology, 2002, 27(6): 949-959.
[10] 万砚, 谢利娜, 王艺明. 抗抑郁剂对去卵巢抑郁模型大鼠色氨酸羟化酶2和血清素的影响[J]. 中华行为医学与脑科学杂志, 2016, 25(5): 416-421.
[11] OSTADKARAMPOUR M, PUTNINS EE. Monoamine oxidase inhibitors: a review of their anti-inflammatory therapeutic potential and mechanisms of action[J]. Front Pharmacol, 2021, 12: 676239.
[12] 贾铷, 芦锰, 陈燕, 等. 解郁胶囊对药物所致抑郁模型小鼠的影响[J]. 中医学报, 2018, 33(2): 278-281.
[13] 周燕, 武新安, 邓毅. 药物转运体与代谢酶间的协作关系对肠肝药物处置的影响[J]. 药学学报, 2020, 55(8): 1762-1767.
[14] 陈红. 长期高强度运动可能预防高血压还是可能诱发高血压?[J]. 中华高血压杂志, 2019, 27(6): 503-511.
[15] 代地林, 吴园, 包明威. 单胺氧化酶A介导的活性氧簇在心血管疾病中的作用[J]. 生物技术进展, 2023, 13(4): 542-546.
[16] 吴晨蕾, 王孟飞, 周荣易. 氧化应激在注意缺陷多动障碍发病机制中的研究进展[J]. 中国当代儿科杂志, 2024, 26(2): 201-206.
[17] 龚胜兰, 富文俊, 黄彬青, 等. 抑郁症海马神经可塑性损伤机制探讨及丹栀逍遥散调控作用的研究进展[J]. 辽宁中医杂志, 2016, 43(3): 663-666.
[18] 郭沉. SST中间神经元功能降低对抑郁症的影响[J]. 心理学进展, 2019(10): 1767-1777.
[19] 费慧芝, 王涵, 胡小娅, 等. 帕罗西汀抗抑郁作用涉及改善氧化应激状态、HPA轴功能和海马脑源性神经营养因子表达[J]. 中国临床药理学与治疗学, 2012, 17(10): 1137-1142.
[20] ATES O, CAYLI SR, GURSES I, et al. Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury[J]. J Clin Neurosci, 2007, 14(7): 658-665.
[21] MA WN, LV L, GUO JG, et al. Effects of Xuesaitong on the pharmacokinetics of losartan: an in vivo UPLC-MS/MS study[J]. Evid Based Complementary Altern Med, 2019, 2019: 8373476.
[22] BRUCKNER BA, AMMINI CV, OTAL MP, et al. Regulation of brain glucose transporters by glucose and oxygen deprivation[J]. Metabolism, 1999, 48(4): 422-431.
[23] 张薇, 李传玉, 张波. 氧化应激影响中枢谷氨酸神经递质系统诱发抑郁症[J]. 中国生物化学与分子生物学报, 2024, 40(10): 1352-1361.
[24] 李会涛, 李剑男, 张桐, 等. 酸枣仁皂苷A对抑郁小鼠行为及突触可塑性相关蛋白的作用[J]. 现代食品科技, 2024, 40(2): 36-43.
[25] 袁莹, 齐艺彤, 林佳. 淫羊藿主要化学成分及其药理作用研究进展[J]. 生物医学, 2024, 14(4): 616-623.

基金资助

国家“重大新药创制”科技重大专项资助项目(2018ZX09731020)