Protective Effects of Cannabinoid Type 2 Receptor Activation Against Microglia Overactivation and Neuronal Pyroptosis in Sepsis-Associated Encephalopathy

Abstract

Sepsis-associated encephalopathy (SAE) has close association with long-term cognitive deficits, resulting in increased mortality. The mechanism of SAE is complicated, including excessive microglial activation and neuroinflammation. Cannabinoid type 2 receptor (CB2R) has been proved to be effective in neuronal protection and survival promotion. Microglia play a role in CB2R mediated neuronal protection when neurons are exposed to noxious stimuli. Pyroptosis is a type of programmed proinflammatory cell death. However, the underlying mechanisms involved in this process still remain to be explored. Here, the SAE model was derived from cecal ligation and puncture (CLP). Tests used to evaluate behavior phenotypes included the open-field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assays (ELISA), Western blotting, and immunofluorescence staining were performed to detect cell injury, cytokine, CB2R and pyroptosis-associated protein expression. Conclusion from these results, we conclude that CLP could induce microglia hyperactivation and neuronal pyroptosis, aggravating brain tissue destruction and cognitive dysfunction. The CB2R-specific agonist HU308 could have protective effects against SAE by inhibiting microglia activity and neuronal pyroptosis. This study provides a new therapeutic option for the treatment of SAE.