基于CREB/PGC-1α通路探讨石菖蒲挥发油调节犬尿氨酸途径缓解抑郁症的作用及机制

Kynurenine pathway dysfunction has a plethora of effects that could contribute to depression. Our previous study presented that the volatile oil extracted from Acori Tatarinowii Rhizoma showed significant anti-depressant effects in mice. It was able to modulate the levels of kynurenine and kynurenic acid in vivo as well as induce the expression of PGC-1α and kynurenine aminotransferases in skeletal muscle. Meanwhile, in C2C12 cells, the application of the volatile oil could increase the expression of kynurenine aminotransferases via CREB/PGC-1α. These results indicated that the anti-depressant effect of the volatile oil might be closely correlated to CREB/PGC-1α and peripheral kynurenine pathway. Therefore, we aimed to investigate the anti-depressant effects of the volatile oil and the underlying mechanism. The major contents include：(1) verify the effects of the volatile oil on anti-depression and peripheral kynurenine pathway in a series of depressed animal and cell models; (2) elucidate the intervention effect of the volatile oil on CREB/PGC-1α; (3) reveal the potential interactions among the components of the volatile oil and illustrate the integrated effects. The results will suggest the relationship among CREB/PGC-1α, peripheral kynurenine pathway and depression, provide new strategies for anti-depression and contribute data to the study of the volatile oil from Acori Tatarinowii Rhizoma.

抑郁症是危害人类身心健康的重大疾病，其发病机制与犬尿氨酸途径异常密切相关。申请人发现石菖蒲挥发油改善慢性应激抑郁症效果显著，其可调节抑郁小鼠体内犬尿氨酸和犬尿喹啉酸水平，上调小鼠骨骼肌PGC-1α和犬尿氨酸转氨酶表达。同时，在细胞水平研究中，挥发油可通过CREB/PGC-1α影响犬尿氨酸转氨酶的表达，提示其抗抑郁作用与干预外周犬尿氨酸途径、CREB/PGC-1α通路有关。本项目拟深入开展以下内容：（1）建立抑郁症相关动物、细胞模型，评价石菖蒲挥发油缓解抑郁症的作用及对外周犬尿氨酸途径的影响；（2）结合RNA干扰和过表达技术，阐明挥发油对CREB/PGC-1α的干预作用，发现挥发油的调节机制；（3）研究挥发油成分的交互作用，反映挥发油的整体功效。研究成果将揭示CREB/PGC-1α通路、外周犬尿氨酸途径与抑郁症的关系，从犬尿氨酸代谢角度为抑郁症防治提供新策略，为石菖蒲挥发油抗抑郁研究提供数据支撑。

犬尿氨酸积累会导致脑损伤，引发抑郁症。石菖蒲是一种广泛用于治疗神经系统疾病的中药，其挥发油是石菖蒲的主要活性部位。本研究从骨骼肌犬尿氨酸代谢方面探讨其对抑郁症的改善作用。石菖蒲挥发油减轻了慢性应激引起的小鼠神经毒性并增强了对抑郁症的抵抗力，这可能是通过调节PGC-1α和犬尿氨酸氨基转移酶表达促进骨骼肌犬尿氨酸代谢清除，使犬尿氨酸转化为犬尿喹啉酸以防止犬尿氨酸积累。在成肌细胞中，石菖蒲挥发油通过cAMP/CREB调节PGC-1α，上调犬尿氨酸氨基转移酶表达，增加犬尿氨酸代谢清除，该作用依赖于PGC-1α。甲基丁香酚和β-细辛醚是石菖蒲挥发油的主要成分，可分别激活腺苷酸环化酶和抑制磷酸二酯酶4，从而协同激活cAMP/CREB和PGC-1α。这些结果表明，石菖蒲挥发油调节PGC-1α表达，促进了肌肉犬尿氨酸代谢清除，且其活性成分对犬尿氨酸的清除具有协同作用，提示调节犬尿氨酸代谢是药物干预抑郁症的一种方式，为石菖蒲挥发油抗抑郁研究与开发提供数据支撑。