Astragalin Exerted Antidepressant-like Action through SIRT1 Signaling Modulated NLRP3 Inflammasome Deactivation

Abstract

Inflammation plays a key role in the pathogenesis of depression and antidepressant therapies. Astragalin (AST) is a bioactive flavonoid that possesses an anti-inflammatory property. However, the antidepressant action of astragalin has not been addressed. In this study, we explored the antidepressant effects of astragalin and its underlying mechanism. Our results showed that AST significantly improved the behavioral defects in chronic unpredictable mild stress (CUMS) model, promoted SIRT1 expression, and decreased the protein levels of NF-κB p65, NLRP3, cleaved capase-1, cleaved IL-1β and cleaved gasdermin D in the hippocampus. Immunohistochemistry revealed AST mitigated CUMSinduced microglia overactivation. In vitro, AST profoundly increased the cell viability in lipopolysaccharides (LPS) and adenosine triphosphate (ATP) treated BV2 cells, with upregulated SIRT1 expression and downregulated protein levels of nuclear NF-κB p65, NLRP3, cleaved capase-1, and cleaved gasdermin D. Declined cleavage of gasdermin D was observed after AST administration in immunocytochemistry. Nevertheless, the in vivo and in vitro effects of AST were compromised by SIRT1 inhibitor EX-527. These results indicated that AST possessed an antidepressant property, which was dependent on SIRT1 signaling modulated NLRP3 inflammasome deactivation.

Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression

“…Moreover, emerging data have shown that plant-derived compounds can exert neuroprotective effects that prevent neurological disorders in depression. For instance, ganoderic acid A [ 227 ], asperosaponin VI [ 228 ], 20( S )-protopanaxadiol [ 229 ], scutellarin [ 230 ], astragalin [ 231 ], hesperidin [ 232 ], 5- O -methylvisammioside [ 233 ], ginkgolide B [ 234 ], leonurine [ 235 ], ferulic acid [ 236 ], and (+)-sesamin [ 69 ] were found to inactivate microglia in stress-induced depression models. Recent information concerning the antidepressant activity of phytochemicals through regulation of microglial polarization is illustrated in Table 2 .…”

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

“…These results indicated that Astragaline displayed antidepressant dependent on SIRT1-activation modulated NLRP3 inflammasome deactivation. [232] 4.13.14. Arctiin Arctiin (209, Figure 27) was a major bioactive component derived from Fructus arctii and possessed neuroprotective and anti-inflammatory activities.…”

“…These results indicated that Astragaline displayed antidepressant dependent on SIRT1‐activation modulated NLRP3 inflammasome deactivation. [ 232 ]…”

Pharmacogenetic‐based management of depression: Role of traditional Persian medicine

“…• Astragalin /À ! anti-depressive activity via SIRT1 signaling pathway (Tong et al, 2020) • Apigenin /FST, TST and sucrose preference test, western blot analysis ! anti-depressant activity via promoting autophagy (AMPK/mTOR signaling pathway) (X.…”