Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin

Qiang-Song Wang; Kuo Yan; Kuang-Dai Li; Li-Na Gao; Xu Wang; Haibo Liu; Zuoguang Zhang; Kefeng Li; Yuan-Lu Cui

doi:10.1016/j.phymed.2021.153735

Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin

Phytomedicine. 2021 Nov:92:153735. doi: 10.1016/j.phymed.2021.153735. Epub 2021 Sep 9.

Authors

Qiang-Song Wang¹, Kuo Yan², Kuang-Dai Li², Li-Na Gao², Xu Wang³, Haibo Liu⁴, Zuoguang Zhang⁵, Kefeng Li⁶, Yuan-Lu Cui⁷

Affiliations

¹ Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China.
² Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
³ State Key Laboratory of Food Nutrition and Safety, College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
⁴ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China.
⁵ Beijing Wonner Biotech. Co. Ltd., Beijing, 101111, China.
⁶ School of Medicine, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: kli@ucsd.edu.
⁷ Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China. Electronic address: cuiyl@tju.edu.cn.

PMID: 34601221
DOI: 10.1016/j.phymed.2021.153735

Abstract

Background: 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.

Purpose: 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.

Results: 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.

Conclusion: 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.

Keywords: Albiflorin; Antidepressant-like effects; Hippocampus; Neurometabolism.

MeSH terms

Animals
Antidepressive Agents / pharmacology
Bridged-Ring Compounds
Depression* / drug therapy
Disease Models, Animal
Hippocampus
Mice
Phospholipids
Stress, Psychological
Tryptophan*

Substances

Antidepressive Agents
Bridged-Ring Compounds
Phospholipids
albiflorin
Tryptophan