Ketamine protects against sepsis-associated encephalopathy by reverting microglial polarization through suppression of receptor-interacting protein kinase 1-driven signaling

Sepsis-associated encephalopathy (SAE) is an acute condition characterized by neuroinflammation and cerebral dysfunction. Ketamine has been shown to alleviate neuroinflammation. However, little is known about its protective effects against SAE. In this study, we aimed to investigate the neuroprotective effects of ketamine in a mouse model of SAE induced with lipopolysaccharide (LPS). We used necrostatin-1s (Nec-1s), an inhibitor of receptor-interacting protein kinase (RIPK) 1 activity, to deduce the mechanism of action of ketamine in model mice. The mice were monitored for weight loss and signs of cognitive dysfunction using the open field, new object recognition, and tail suspension behavior tests. Tissue and serum samples from the mice were analyzed for levels of pro-inflammatory cytokines (tumor necrosis factor α, interleukin 1β, and interleukin 6) and other markers of inflammation. Ketamine and Nec-1s administration reduced weight loss, cognitive dysfunction, and pro-inflammatory cytokine levels. Ketamine administration also reverted microglial polarization by increasing the expression of arginase-1 and reducing the expression of cluster of differentiation 80. Ketamine downregulated RIPK1-driven signaling by reducing the phosphorylation and expression of RIPK1, RIPK3, and mixed lineage kinase domain-like protein. These findings demonstrate that ketamine protects against SAE by reverting microglial polarization via suppression of RIPK1-driven signaling.