TXNIP/NLRP3 aggravates global cerebral ischemia-reperfusion injury-induced cognitive decline in mice

Global cerebral ischemia/reperfusion (GCI/R) injury poses a risk for cognitive decline, with neuroinflammation considered pivotal in this process. This study aimed to unravel the molecular mechanisms underlying GCI/R injury and propose a potential therapeutic strategy for associated cognitive deficits. Utilizing bioinformatics analysis of a public microarray profile (GSE30655 and GSE80681) in cerebral ischemic mice, it was observed that neuroinflammation emerged as a significant gene ontology item, with an increase in the expression of thioredoxin-interacting protein (TXNIP) and NLRP3 genes. Experimental models involving bilateral occlusion of the common carotid arteries in mice revealed that GCI/R induced cognitive impairment, along with a time-dependent increase in TXNIP and NLRP3 levels. Notably, TXNIP knockdown alleviated cognitive dysfunction in mice. Furthermore, the introduction of adeno-associated virus injection with TXNIP knockdown reduced the number of activated microglia, apoptosis neurons, and levels of oxidative stress and inflammatory cytokines in the hippocampus. Collectively, these findings underscore the significance of TXNIP/NLRP3 in the hippocampus in exacerbating cognitive decline due to GCI/R injury, suggesting that TXNIP knockdown holds promise as a therapeutic strategy. In brief: Using bioinformatics analysis based on GSE30655 and GSE80681 datasets revealed an increase in the expression of genes TXNIP and NLRP3 in mice experiencing ischemia/reperfusion injury. The introduction of TXNIP knockdown via adeno-associated virus injection demonstrated a mitigation of neuroinflammation and cognitive decline induced by global cerebral ischemia/reperfusion injury. This amelioration was associated with microglial activation, mediated by the inhibition of the TXNIP/NLRP3 signaling pathway. Activations were denoted by “+”, inhibitions by “–”, increases by “↑”, and decreases by “↓”. [Display omitted]