Activation of glucagon-like peptide-1 receptor in microglia exerts protective effects against sepsis-induced encephalopathy via attenuating endoplasmic reticulum stress-associated inflammation and apoptosis in a mouse model of sepsis

Sepsis-induced encephalopathy (SAE) is a detrimental complication in patients with severe sepsis, while there is still no effective treatment. Previous studies have elucidated the neuroprotective effects of glucagon-like peptide1 receptor (GLP-1R) agonists. However, the role of GLP-1R agonists in the pathological process of SAE is unclear. Here, we found that GLP-1R was up-regulated in the microglia of septic mice. The activation of GLP-1R with Liraglutide could inhibit endoplasmic reticulum stress (ER stress) and associated inflammatory response as well as apoptosis triggered by LPS or tunicamycin (TM) in BV2 cells. In vivo experiments confirmed the benefits of Liraglutide in the regulation of microglial activation, ER stress, inflammation, and apoptosis in the hippocampus of septic mice. Additionally, the survival rate and cognitive dysfunction of septic mice were also improved after Liraglutide administration. Mechanically, cAMP/PKA/CREB signaling is involved in the protection of ER stressinduced inflammation and apoptosis in cultured microglial cells under LPS or TM stimulations. In conclusion, we speculated that GLP-1/GLP-1R activation in microglia might be a potential therapeutic target for the treatment of SAE.

Automated summary

The activation of GLP-1R with Liraglutide can inhibit ER stress, inflammation, and apoptosis in microglia, improving the pathological process of SAE. In vivo experiments confirmed the benefits of Liraglutide in regulating microglial activation and improving survival rate and cognitive dysfunction in septic mice.