Knowledgebase-Driven Exploration and Experimental Verification of Simvastatin's Inhibitory Impact on P2X7/NLRP3 Inflammasome Pathway

Depression is a mental health disorder and is the fourth most prevalent disease. Previous studies have suggested that statins are involved in the reduction of neuroinflammation. However, the potential mechanism for this relationship is unclear. The current study aimed to elucidate this by examining the effects of simvastatin on the P2X7/NLRP3 pathway in rats exposed to chronic mild stress (CMS). To achieve this goal, a depression database was first constructed, and simvastatin was used as an input to predict potential targets using machine/deep learning methods. Interestingly, the P2X7/NLRP3 pathway was predicted as a potential target for simvastatin. Subsequently, a depression rat model was established by inducing CMS for 4 weeks. Behavioral changes were detected via a sucrose preference test and forced swim test. The depression rats were then treated with simvastatin (10 mg/kg/day) for 14 days. Following treatment, changes in behavior and the activation of the NLRP3/ASC/caspase-1 inflammasome pathway in the depression model rats were observed. The P2X7 agonist (ATP) and selective P2X7 antagonist brilliant blue G (BBG) were also used for in vivo intervention. Data from the experiment showed that treatment with simvastatin and BBG significantly reduced the depressive-like behaviors in depression model rats, as well as the protein and mRNA expression levels of P2X7 and NLRP3 inflammasome. The protein and mRNA levels of the pro-inflammatory cytokine interleukin-1β significantly increased. These results demonstrate that simvastatin exerted an antidepressant-like effect in the CMS model of rats, and this effect was dependent on the inhibition of the P2X7/NLRP3 inflammasome pathway.