Table1_Zhi-Zi-Chi Decoction Reverses Depressive Behaviors in CUMS Rats by Reducing Oxidative Stress Injury Via Regulating GSH/GSSG Pathway.pdf

Depression is one of the main diseases that lead to disability and loss of ability to work. As a traditional Chinese medicine, Zhi-zi-chi decoction is utilized to regulate and improve depression. However, the research on the antidepressant mechanism and efficacy material basis of Zhi-zi-chi decoction has not been reported yet. Our previous research has found that Zhi-Zi-chi decoction can reduce glutamate-induced oxidative stress damage to PC 12 cells, which can exert a neuroprotective effect, and the antidepressant effect of Zhi-Zi-chi decoction was verified in CUMS rat models. In this study, the animal model of depression was established by chronic unpredictable mild stimulation combined with feeding alone. The brain metabolic profile of depressed rats was analyzed by the method of metabolomics based on ultra-performance liquid chromatography-quadrupole/time-of-flight mass. 26 differential metabolites and six metabolic pathways related to the antidepressant of Zhi-zi-chi decoction were screened and analyzed. The targeted metabolism of the glutathione metabolic pathway was analyzed. At the same time, the levels of reactive oxygen species, superoxide dismutase, glutathione reductase, glutathione peroxidase in the brain of depressed rats were measured. Combined with our previous study, the antioxidant effect of the glutathione pathway in the antidepressant effect of Zhi-zi-chi decoction was verified from the cellular and animal levels respectively. These results indicated that Zhi-zi-chi decoction exerted a potential antidepressive effect associated with reversing the imbalance of glutathione and oxidative stress in the brain of depressed rats.

抑郁症是导致残疾与劳动能力丧失的主要疾病之一。作为一味传统中药，栀子豉汤（Zhi-zi-chi decoction）可用于调节与改善抑郁症状。然而，目前尚未有关于栀子豉汤抗抑郁作用机制及药效物质基础的研究报道。本团队前期研究发现，栀子豉汤可减轻谷氨酸诱导的PC12细胞氧化应激损伤，发挥神经保护作用，且其抗抑郁功效已在慢性不可预见性温和应激（chronic unpredictable mild stress, CUMS）大鼠模型中得到验证。本研究采用慢性不可预见性温和刺激结合单笼饲养的方式构建抑郁动物模型，通过基于超高效液相色谱-四极杆/飞行时间质谱（ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry）的代谢组学方法分析抑郁大鼠的脑部代谢谱，最终筛选并分析得到26个差异代谢物及6条与栀子豉汤抗抑郁作用相关的代谢通路。此外，本研究对谷胱甘肽代谢通路开展了靶向代谢组学分析。同时，本研究检测了抑郁大鼠脑组织内活性氧（reactive oxygen species, ROS）、超氧化物歧化酶（superoxide dismutase, SOD）、谷胱甘肽还原酶及谷胱甘肽过氧化物酶的水平。结合前期研究结果，本研究分别从细胞与动物层面验证了谷胱甘肽代谢通路在栀子豉汤抗抑郁作用中的抗氧化效应。上述结果表明，栀子豉汤可通过逆转抑郁大鼠脑组织内谷胱甘肽失衡与氧化应激状态，发挥潜在的抗抑郁作用。