Protective effects of cannabinoid type 2 receptor against microglia overactivation and neuronal pyroptosis in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) has close association with long-term cognitive deficits, resulting in increased mortality. The mechanism of SAE is complicate, including excessive microglial activation and neuroinflammation. Pyroptosis is a type of proinflammatory cell death program. 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. However, the underlying mechanisms involved in this process still remain to be explored. Previous studies have demonstrated that CB2R can reduce sepsis-induced lung injury by inhibiting pyroptosis. Here, SAE model was established by cecal ligation and puncture (CLP). Open field test (OFT), novel object recognition test (NORT), and morris water maze (MWM) test were performed to assess cognitive function. Brain samples were obtained to detect cell injury, cytokine, CB2R and pyroptosis-associated protein expression by Hematoxylin-Eosin (HE) Staining, Enzyme-linked immunosorbent assay (ELISA), Western blotting and Immunofluorescence staining. CLP could induce microglia hyperactivation and neuronal pyroptosis, aggravating brain tissue destruction and cognitive dysfunction. The activation of CB2R could have a protective effect against SAE by inhibiting microglia activity and neuronal pyroptosis. This will provide a new therapeutic option for the treatment of SAE.