Mechanism of lily bulb and Rehmannia decoction in the treatment of lipopolysaccharide-induced depression-like rats based on metabolomics study and network pharmacology

Pharm Biol. 2022 Dec;60(1):1850-1864. doi: 10.1080/13880209.2022.2121843.

Abstract

Context: Lily bulb and Rehmannia decoction (LBRD), consisting of Lilium henryi Baker (Liliaceae) and Rehmannia glutinosa (Gaertn) DC (Plantaginaceae), is a specialized traditional Chinese medicine formula for treating depression. However, the underlying mechanisms, especially the relationship between LBRD efficacy and metabolomics, remains unclear.

Objective: This study was aimed to investigate the metabolic mechanism of LBRD in treating depression.

Materials and methods: Network pharmacology was conducted using SwissTargetPrediction, DisGeNET, DrugBank, Metascape, etc., to construct component-target-pathway networks. The depression-like model was induced by intraperitoneal injection with lipopolysaccharide (LPS) (0.3 mg/kg) for 14 consecutive days. After the administration of LBRD (90 g/kg) and fluoxetine (2 mg/kg) for 14 days, we assessed behaviour and the levels of neurotransmitter, inflammatory cytokine and circulating stress hormone. Prefrontal metabolites of rats were detected by using liquid chromatography-mass spectrometry metabolomics method.

Results: The results of network pharmacology showed that LBRD mainly acted on neurotransmitter and second messenger pathways. Compared to the model group, LBRD significantly ameliorated depressive phenotypes and increased the level of 5-HT (13.4%) and GABA (24.8%), as well as decreased IL-1β (30.7%), IL-6 (32.8%) and TNF-α (26.6%). Followed by LBRD treatment, the main metabolites in prefrontal tissue were contributed to retrograde endocannabinoid signalling, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, autophagy signal pathway, etc.

Discussion and conclusions: LBRD were effective at increasing neurotransmitter, attenuating proinflammatory cytokine and regulating glycerophospholipid metabolism and glutamatergic synapse, thereby ameliorating depressive phenotypes. This research will offer reference for elucidating the metabolomic mechanism underlying novel antidepressant agents contained LBRD formula.

Keywords: Traditional Chinese medicine formula; depressive disorder; medial prefrontal cortex; metabolic components.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Cytokines
  • Depression / chemically induced
  • Depression / drug therapy
  • Drugs, Chinese Herbal* / pharmacology
  • Drugs, Chinese Herbal* / therapeutic use
  • Endocannabinoids
  • Fluoxetine
  • Glycosylphosphatidylinositols
  • Hormones
  • Interleukin-6
  • Lilium*
  • Lipopolysaccharides / toxicity
  • Metabolomics / methods
  • Network Pharmacology
  • Plant Extracts
  • Rats
  • Rehmannia*
  • Serotonin
  • Tumor Necrosis Factor-alpha
  • gamma-Aminobutyric Acid

Substances

  • Antidepressive Agents
  • Cytokines
  • Drugs, Chinese Herbal
  • Endocannabinoids
  • Glycosylphosphatidylinositols
  • Hormones
  • Interleukin-6
  • Lipopolysaccharides
  • Plant Extracts
  • Tumor Necrosis Factor-alpha
  • Fluoxetine
  • rehmannia root
  • Serotonin
  • gamma-Aminobutyric Acid

Grants and funding

This work was supported by National Nature Science Foundation of China [81903948 and 82174117] and Shandong Provincial Natural Science Foundation [ZR2019ZD23]. Furthermore, it was also supported by the Shandong Co-Innovation Centre of Classic TCM Formula, Shandong Province Universities’ Development Plan for Youth Innovation Teams [2019-9-202, 2019-201 and 2019KJK013].