Abstract：
BACKGROUND: Shenfu decoction (SFD) is a classic Chinese medicine prescription that has a strong cardiotonic effect. The combination of ginseng (the dried root of Panax ginseng C. A. Meyer) and Fuzi (processed product of sub-root of Aconitum carmichaeli Debx), the main constituents of SFD, has been reported to improve the pharmacological effect of each other. Moreover, research has shown that the main active components of SFD, ginseng total saponins (GTS) and Fuzi total alkaloids (FTA), have antidepressant activity. However, the effects of these ingredients on depressive-like behavior induced by ovariectomy, a model of menopausal depression, have not been studied.
OBJECTIVE: Our research aims to elucidate the antidepressant-like effects of GTS and FTA compatibility (GF) in ovariectomized mice and the potential mechanisms.
METHODS: To elucidate the antidepressant-like effects of GF in mice in ovariectomy condition, behavioral tests were performed after 7 days of intragastric administration of different doses of GF. Underlying molecular mechanisms of CREB-BDNF, BDNF-mTORC1 and autophagy signaling were detected by western blotting, serum metabolites were examined by UPLC-QE plus-MS and dendritic spine density was determined by Golgi-Cox staining.
RESULTS: GF remarkably decreased the immobility time in the forced swim test. GF also increased levels of pCREB/CREB, BDNF, Akt, mTORC1 and p62 in the prefrontal cortex and hippocampus, as well as decreased LC3-II/LC3-I in the prefrontal cortex and hippocampus of ovariectomized mice. Furthermore, 15 serum differential metabolites (9 of which are lipids and lipid molecules) were identified by metabonomics. Next, the antidepressant-like effects of GF was blocked by rapamycin, an inhibitor of mTORC1. The antidepressant actions of GF on levels of pCREB, mTORC1, LC3-Ⅱ/LC3-Ⅰ and p62 in the prefrontal cortex and the levels of BDNF, Akt, mTORC1 and p62 in the hippocampus were inhibited by rapamycin, and the dendritic spines density was also regulated.
CONCLUSIONS: GF has antidepressant effects in ovariectomized mice, and like other antidepressants, these effects involve activation of BDNF-mTORC1, autophagy regulation and consequent effects on hippocampal synaptic plasticity. Moreover, metabolomic results suggest that GF also has effects on peripheral lipid profiles that may provide potential biomarkers for these antidepressant-like effects. These results indicate that GF is worthy of further exploration as a promising pharmaceutical treatment for depression. This study provides a new direction for the development of new indications for traditional Chinese medicine compounds.
OBJECTIVE: Our research aims to elucidate the antidepressant-like effects of GTS and FTA compatibility (GF) in ovariectomized mice and the potential mechanisms.
METHODS: To elucidate the antidepressant-like effects of GF in mice in ovariectomy condition, behavioral tests were performed after 7 days of intragastric administration of different doses of GF. Underlying molecular mechanisms of CREB-BDNF, BDNF-mTORC1 and autophagy signaling were detected by western blotting, serum metabolites were examined by UPLC-QE plus-MS and dendritic spine density was determined by Golgi-Cox staining.
RESULTS: GF remarkably decreased the immobility time in the forced swim test. GF also increased levels of pCREB/CREB, BDNF, Akt, mTORC1 and p62 in the prefrontal cortex and hippocampus, as well as decreased LC3-II/LC3-I in the prefrontal cortex and hippocampus of ovariectomized mice. Furthermore, 15 serum differential metabolites (9 of which are lipids and lipid molecules) were identified by metabonomics. Next, the antidepressant-like effects of GF was blocked by rapamycin, an inhibitor of mTORC1. The antidepressant actions of GF on levels of pCREB, mTORC1, LC3-Ⅱ/LC3-Ⅰ and p62 in the prefrontal cortex and the levels of BDNF, Akt, mTORC1 and p62 in the hippocampus were inhibited by rapamycin, and the dendritic spines density was also regulated.
CONCLUSIONS: GF has antidepressant effects in ovariectomized mice, and like other antidepressants, these effects involve activation of BDNF-mTORC1, autophagy regulation and consequent effects on hippocampal synaptic plasticity. Moreover, metabolomic results suggest that GF also has effects on peripheral lipid profiles that may provide potential biomarkers for these antidepressant-like effects. These results indicate that GF is worthy of further exploration as a promising pharmaceutical treatment for depression. This study provides a new direction for the development of new indications for traditional Chinese medicine compounds.
摘要：
背景：参附汤（SFD）是一种具有强心作用的经典中药方剂。人参（人参C.A.Meyer的干燥根）和附子（乌头次根的加工产品）的组合，SFD的主要成分，据报道可以改善彼此的药理作用。此外，研究表明，SFD的主要活性成分，人参总皂苷（GTS）和附子总生物碱（FTA），具有抗抑郁活性。然而,这些成分对卵巢切除术引起的抑郁样行为的影响，更年期抑郁症的典范,没有被研究过。
目的：我们的研究旨在阐明GTS和FTA相容性（GF）在卵巢切除小鼠中的抗抑郁样作用及其潜在机制。
方法：为了阐明GF对卵巢切除小鼠的抗抑郁样作用，不同剂量GF灌胃给药7天后进行行为测试。CREB-BDNF的潜在分子机制，通过蛋白质印迹检测BDNF-mTORC1和自噬信号,通过UPLC-QE加MS检查血清代谢产物，通过高尔基Cox染色确定树突棘密度。
结果：GF显著降低了强迫游泳试验的不动时间。GF也增加了pCREB/CREB的水平，BDNF,Akt,前额叶皮质和海马中的mTORC1和p62，以及卵巢切除小鼠前额叶皮质和海马中LC3-II/LC3-I的降低。此外，通过代谢组学鉴定了15种血清差异代谢物（其中9种是脂质和脂质分子）。接下来,雷帕霉素阻断了GF的抗抑郁作用，mTORC1的抑制剂。GF对pCREB水平的抗抑郁作用，mTORC1、LC3-Ⅱ/LC3-Ⅰ和p62在前额叶皮质和BDNF的水平,Akt,雷帕霉素抑制海马中的mTORC1和p62，树突棘密度也受到调节。
结论：GF对去卵巢小鼠具有抗抑郁作用，和其他抗抑郁药一样，这些效应涉及BDNF-mTORC1的激活、自噬调节以及对海马突触可塑性的影响。此外，代谢组学结果提示GF对外周血脂谱也有影响,这可能为这些抗抑郁样作用提供潜在的生物标志物.这些结果表明，GF作为抑郁症的有希望的药物治疗值得进一步探索。本研究为中药复方新适应症的开发提供了新的方向。
目的：我们的研究旨在阐明GTS和FTA相容性（GF）在卵巢切除小鼠中的抗抑郁样作用及其潜在机制。
方法：为了阐明GF对卵巢切除小鼠的抗抑郁样作用，不同剂量GF灌胃给药7天后进行行为测试。CREB-BDNF的潜在分子机制，通过蛋白质印迹检测BDNF-mTORC1和自噬信号,通过UPLC-QE加MS检查血清代谢产物，通过高尔基Cox染色确定树突棘密度。
结果：GF显著降低了强迫游泳试验的不动时间。GF也增加了pCREB/CREB的水平，BDNF,Akt,前额叶皮质和海马中的mTORC1和p62，以及卵巢切除小鼠前额叶皮质和海马中LC3-II/LC3-I的降低。此外，通过代谢组学鉴定了15种血清差异代谢物（其中9种是脂质和脂质分子）。接下来,雷帕霉素阻断了GF的抗抑郁作用，mTORC1的抑制剂。GF对pCREB水平的抗抑郁作用，mTORC1、LC3-Ⅱ/LC3-Ⅰ和p62在前额叶皮质和BDNF的水平,Akt,雷帕霉素抑制海马中的mTORC1和p62，树突棘密度也受到调节。
结论：GF对去卵巢小鼠具有抗抑郁作用，和其他抗抑郁药一样，这些效应涉及BDNF-mTORC1的激活、自噬调节以及对海马突触可塑性的影响。此外，代谢组学结果提示GF对外周血脂谱也有影响,这可能为这些抗抑郁样作用提供潜在的生物标志物.这些结果表明，GF作为抑郁症的有希望的药物治疗值得进一步探索。本研究为中药复方新适应症的开发提供了新的方向。
