Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
Phytomedicine. 2021 Nov;92:153735. doi: 10.1016/j.phymed.2021.153735. Epub 2021 Sep 9.
Current antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown.
The objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach.
We found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis.
Our study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.
由于抗抑郁药的临床起效时间延迟和抑郁症的异质性，目前的抗抑郁治疗仍不尽人意。针对失调的神经代谢途径可能为抑郁症的治疗提供一种新的治疗方法。白芍苷是从牡丹根（白芍）中分离得到的一种植物药，具有极好的临床耐受性。到目前为止，白芍苷在不同类型抑郁症中的抗抑郁样活性及其对神经代谢的影响尚不清楚。
本研究旨在探讨白芍苷在三种常见抑郁症动物模型中的快速抗抑郁样作用，并采用多组学方法阐明其作用的药物代谢机制。
我们发现白芍苷在慢性不可预测轻度应激（CUMS）、嗅球切除术（OBX）和脂多糖（LPS）诱导的小鼠抑郁症模型中产生快速抗抑郁样作用。通过结合代谢组学、脂质组学和转录组学的系统方法，我们表明白芍苷的治疗效果与快速恢复三种抑郁症模型中海马中一组共同的代谢异常高度相关，包括磷脂和色氨酸代谢。进一步的机制分析表明，白芍苷通过抑制海马细胞质型 PLA2（cPLA2）使磷脂代谢的代谢失调正常化。此外，白芍苷通过抑制 cPLA2 过表达纠正色氨酸代谢中异常的犬尿氨酸途径，通过 cPLA2-蛋白激酶 B（Akt1）-吲哚胺 2,3-双加氧酶 1（IDO1）调节环，引导色氨酸分解代谢向更多的海马 5-羟色胺生物合成。
本研究有助于更好地理解抑郁症代谢机制的同质性，并为通过靶向失调的神经代谢途径快速治疗抑郁症建立了概念验证。
