Abstract
Puerarin has been reported as a potential agent for neuro-inflammatory disorders. However, there have been no reports of using puerarin for the treatment of depression based on Toll-like receptor 4 (TLR4)–mediated inflammatory injury. In this study, we evaluated the protective effects of puerarin on depression-like rats induced by a high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS). The mechanism was screened by lipidomics and molecular docking and confirmed by in vivo tests. Puerarin treatment significantly improved 1% sucrose preference and ameliorated depression-like behavior in the open-field test. The antidepressive effects of puerarin were associated with decreased pro-inflammatory cytokine production, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and increased anti-inflammatory cytokine levels (IL-10) in rat hippocampal tissues and plasma. Hematoxylin–eosin (H&E), immunofluorescence staining, and Western blotting results displayed that puerarin alleviated inflammatory injury by suppressing TLR4 expression and by repairing the intestine mucus barrier via enhancing the expression of claudin-1 and occludin. Non-targeted lipidomics analysis showed that the most significantly different metabolites modified by puerarin were phospholipids. Puerarin treatment–altered biomarkers were identified as PC (15:1/20:1), PE (15:1/16:1), and PI (18:2/20:1) in comparison with the HFD/CUMS group. Molecular docking modeling revealed that puerarin could bind with cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), which play central roles in TLR4-mediated phospholipid metabolism. In vivo, puerarin treatment decreased the enzyme activities of cPLA2 and COX-2, resulting in lower production of prostaglandin E2 (PGE2) in hippocampal and intestinal tissues. In conclusion, puerarin treatment reverses HFD/CUMS-induced depression-like behavior by inhibiting TLR4-mediated intestine mucus barrier dysfunction and neuro-inflammatory damages via the TLR4/cPLA2/COX-2 pathway.
Highlights
Depression is characterized by long-term depressed mood and loss of interest and pleasure
Puerarin (>98%) was purchased from Jiangsu Yongjian Pharmaceutical Technology Co., Ltd. (Jiangsu, China); fluoxetine hydrochloride (Prozac) was purchased from Eli Lilly and Company; simvastatin was obtained from Dalian Meilun Biotech Co., Ltd. (Dalian, China); rat enzyme-linked immunosorbent assay (ELISA) kits of IL-6 and TNFα were purchased from PeproTech (Rocky Hill, United States); the IL-10 rat ELISA kit was purchased from eBioscience (San Diego, United States); the BCA Protein Assay Kit was purchased from Pierce (Rochford,United States); Goat Anti-Mouse IgG
In order to investigate the protective effect of puerarin on depression, an high-fat diet (HFD)/chronic unpredictable mild stress (CUMS)-induced depression-like rat model was used
Summary
Depression is characterized by long-term depressed mood and loss of interest and pleasure. The proportion of the global population suffering from major depression has increased to more than 300 million people (World Health, 2017). A major depression-induced reduction in lifespan is due to the significant increase in vulnerability to major medical disorders, such as stroke, diabetes, cancer, and cardiovascular disease (Beurel et al, 2020). Several hypotheses have been developed for the pathologic process of depressive disorder, including the monoamine hypothesis (Hirschfeld, 2000), glutamate hypothesis (Sanacora et al, 2012), and hypothalamic–pituitary–adrenocortical (HPA) axis hypothesis (Holsboer, 2000). A reflection of the 20-year studies indicates that increased inflammation and hyperactivity of the HPA axis are two of the most consistent biological findings in major depression (Pariante, 2017).
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