Puerarin Alleviates Depression-Like Behavior Induced by High-Fat Diet Combined With Chronic Unpredictable Mild Stress via Repairing TLR4-Induced Inflammatory Damages and Phospholipid Metabolism Disorders

Li-Na Gao; Maocai Yan; Lirun Zhou; Jian'an Wang; Chunmei Sai; Yingjie Fu; Yang Liu; Lin Ding

doi:10.3389/fphar.2021.767333

Puerarin Alleviates Depression-Like Behavior Induced by High-Fat Diet Combined With Chronic Unpredictable Mild Stress via Repairing TLR4-Induced Inflammatory Damages and Phospholipid Metabolism Disorders

Front Pharmacol. 2021 Dec 15:12:767333. doi: 10.3389/fphar.2021.767333. eCollection 2021.

Authors

Li-Na Gao^{1

2}, Maocai Yan¹, Lirun Zhou^{1

3}, Jian'an Wang¹, Chunmei Sai¹, Yingjie Fu¹, Yang Liu¹, Lin Ding¹

Affiliations

¹ College of Pharmacy, Jining Medical University, Rizhao, China.
² Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China.
³ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

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.

Keywords: Toll-like receptor 4; cyclooxygenase 2; cytosolic phospholipases A2; depression; inflammation; puerarin.