Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin
| Autor: | Zuoguang Zhang, Xu Wang, Kuo Yan, Haibo Liu, Li-Na Gao, Kefeng Li, Yuan-Lu Cui, Kuang-Dai Li, Qiang-Song Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Bridged-Ring Compounds
Kynurenine pathway Pharmaceutical Science Hippocampus AKT1 Pharmacology Hippocampal formation Mice Metabolomics Animal models of depression Drug Discovery Lipidomics Medicine Animals Phospholipids business.industry Kinase Depression Tryptophan Antidepressive Agents Disease Models Animal Complementary and alternative medicine Molecular Medicine business Stress Psychological |
| Zdroj: | Phytomedicine : international journal of phytotherapy and phytopharmacology. 92 |
| ISSN: | 1618-095X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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