Inflammation plays a vital role in the pathophysiology of depression. However, the underlying pathological mechanism is still elusive. 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). 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).
Moreover, 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). In addition to the extraordinary economic burden, the tragedy of suicide contributes to the high mortality of this disorder. Currently, the proportion of the global population suffering from major depression has increased to more than 300 million people ( World Health, 2017). Thus, depression is highly heterogeneous. The phenotype and course of a depressive episode is singular, recurring, or chronic ( Gururajan et al., 2019). 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.ĭepression is characterized by long-term depressed mood and loss of interest and pleasure. In vivo, puerarin treatment decreased the enzyme activities of cPLA2 and COX-2, resulting in lower production of prostaglandin E 2 (PGE 2) in hippocampal and intestinal tissues. 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.
PCAD 2001 FORUM PC
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. Non-targeted lipidomics analysis showed that the most significantly different metabolites modified by puerarin were phospholipids. 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. 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. Puerarin treatment significantly improved 1% sucrose preference and ameliorated depression-like behavior in the open-field test. The mechanism was screened by lipidomics and molecular docking and confirmed by in vivo tests. 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). However, there have been no reports of using puerarin for the treatment of depression based on Toll-like receptor 4 (TLR4)–mediated inflammatory injury.
Puerarin has been reported as a potential agent for neuro-inflammatory disorders. 3Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.2Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China.
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