Exenatide attenuates neuroinflammation and rescues sepsis-induced depressive behavior and cognitive dysfunction in a...

Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remain unelucidated. This study explored whether exenatide (Exe) alleviates depressive-like behaviors and cognitive deficits in a murine SID model.

SID mice were intraperitoneally administered exenatide (1 mg/kg/day) or vehicle for 14 days. Behavioral assessments included the Open Field Test, Forced Swimming Test, Tail Suspension Test, Sucrose Preference Test, Morris Water Maze, Novel Object Recognition, Novel Location Recognition, Three-Chamber Social Interaction Test, and IntelliCage system. Murine sepsis clinical scores and Nissl staining evaluated the model behaviorally and histologically. High-performance liquid chromatography quantified hippocampal 5-hydroxytryptamine (5-HT) and dopamine (DA), while enzyme-linked immunosorbent assay measured hippocampal and plasma biomarkers.

Chronic exenatide treatment significantly reduced immobility time in the Forced Swimming and Tail Suspension Tests, improved cognitive performance in the Morris Water Maze, enhanced sucrose preference, and boosted novel object/location recognition and social interaction. Exenatide downregulated tumor necrosis factor-α, interleukin-6, and adrenocorticotropic hormone levels, while upregulating 5-HT, DA, phosphorylated cAMP response element-binding protein, and brain-derived neurotrophic factor.

Exenatide exerts antidepressant-like and pro-cognitive effects in SID mice, likely via GLP-1 receptor-mediated suppression of hippocampal inflammation and promotion of neuroplasticity. GLP-1 analogues are promising dual-action therapeutics for comorbid depression and cognitive deficits, pending validation in further models and clinical trials.