Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARγ/NF-κB/NLRP3 inflammasome axis

• Published in: Acta pharmacologica Sinica 2018-10, Vol.39 (10), p.1559-1570
• Main Authors: Song, Mei-ting, Ruan, Jie, Zhang, Ru-yi, Deng, Jie, Ma, Zhan-qiang, Ma, Shi-ping
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anti-Inflammatory Agents - therapeutic use; Antidepressive Agents - therapeutic use; Apoptosis; Astragalus membranaceus; Biomedical and Life Sciences; Biomedicine; Caspase; Caspase-1; Depressive Disorder, Major - drug therapy; Etiology; Hippocampus; Hippocampus - metabolism; IL-1β; Immunoglobulins; Immunology; Inflammasomes; Inflammasomes - drug effects; Inflammation; Inflammation - drug therapy; Inhibition; Injection; Internal Medicine; Lipopolysaccharides; Locomotor activity; Male; Medical Microbiology; Mental depression; Mice; Mice, Inbred ICR; NF-κB protein; Pharmacology/Toxicology; Phosphorylation; Pyrin protein; Rodents; Saponins - therapeutic use; Signal Transduction - drug effects; Sucrose; Sugar; Triterpenes - therapeutic use; Tumor necrosis factor-α; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.208

Major depressive disorder is a common but devastating mental disorder, and recent evidence shows that neuroinflammation may play a pivotal role in the etiology of depression. Astragaloside IV (AS-IV) is an active component purifed from Astragalus membranaceus (Fisch) Bge, which has shown anti-inflammatory, anti-oxidative and anti-apoptotic effects. In this study, we explored whether AS-IV produced antidepressant effects via its inhibition of neuroinflammation in mouse models of depression. Depressive-like behaviors including decreased sucrose consumption, reduced locomotor activity and increased immobility time were induced in mice using repeated restraint stress (RRS). We found that administration of AS-IV (16, 32 and 64 mg·kg -1 ·d -1 , ig) significantly attenuated RRS-induced depressive-like behaviors. Furthermore, AS-IV administration significantly reduced the levels of TNF-α and IL-1β, increased PPARγ expression and GSK3β phosphorylation, decreased NF-κB phosphorylation, and reduced NOD-, LRR- and pyrin domain-containingprotein 3 (NLRP3) inflammasome and caspase-1 p20 generation in the hippocampus of the mice. LPS-induced depression-like behaviors were induced by LPS injection (1 mg·kg -1 ·d -1 , ip), which were ameliorated by administration of AS-IV (20, 40 mg·kg -1 ·d -1 , ig). The results of the LPS-induced mouse model were in accordance with those acquired from the RRS-induced mouse model: LPS injection significantly increased TNF-α and IL-1β expression in the mouse hippocampus, which was reversed by administration of AS-IV. Moreover, administration of AS-IV significantly increased PPARγ expression and GSK3β phosphorylation, and decreased NF-κB phosphorylation and NLRP3 inflammasome. These results suggest that AS-IV is a potential drug against depression, and its antidepressant effects are partially mediated by inhibition of neuroinflammation via the upregulation of PPARγ expression.