Ghrelin Inhibits Inflammasomes Activation in Astrocytes, Alleviates Pyroptosis, and Prevents Lipopolysaccharide-induced Depression-like Behavior in Mice

Depression is the leading cause of disability worldwide and places a significant burden on society. Neuroinflammation is closely associated with the pathophysiology of depression. Increasing evidence suggests that astrocytes, as the most abundant glial cells in the brain, are involved in the occurrence and development of depression due to morphological abnormalities and dysfunction. Astrocytes express the NOD-like receptor protein 2 (NLRP2) and NLRP3 inflammasomes, and the activation of inflammasomes induces pyroptosis. Ghrelin, a gastrointestinal peptide, plays vital role in regulating inflammation and alleviating stress. Therefore, we proposed a hypothesis that ghrelin inhibits the activation of inflammasomes on astrocytes, reduces pyroptosis, and consequently prevents depression. We used lipopolysaccharide (LPS)-induced mouse depression model and cultured primary astrocytes in vitro to explore the mechanism of the antidepressant effect of ghrelin. Our results showed that ghrelin effectively inhibited acute inflammatory responses and damage in the hippocampus and prefrontal cortex. The activation of NLRP2 and NLRP3 in astrocytes induced by LPS was significantly inhibited by ghrelin. Pretreatment with ghrelin effectively suppressed LPS-induced upregulation of pyroptosis-related proteins and mRNA. Ghrelin alleviated cell membrane pore formation and cell swelling, ultimately improved LPS-induced depression-like behavior. In vitro, ghrelin prevented the LPS-induced upregulation of pyroptosis-related proteins and mRNA expression in astrocytes, and inhibited the initiation and assembly of NLRP2 and NLRP3. Ghrelin exhibits antidepressant effects, inhibits inflammasomes activation in astrocytes, and prevents pyroptosis, suggesting a novel strategy for treating depression. This groundbreaking study reveals new avenues for targeting potential therapeutic interventions to alleviate depression.