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

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

  • Neuroscience. 2026 Apr 16:600:112-129. doi: 10.1016/j.neuroscience.2026.02.033.
Shenhai Liu 1,  Qiao Chen 2,  Hui Liu 3,  Zihang Chen 4,  Na Ding 5,  Tao Sun 6,  Lin Wang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Early Warning and Intervention of Multiple Organ Failure, Ministry of Education of the People's Republic of China, and Department of General Intensive Care Unit, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China. Electronic address: [email protected].
  • 2 Department of Ophthalmology, the Jingzhou Hospital Affiliated to Yangtze University, Jingzhou 434000, China. Electronic address: [email protected].
  • 3 Children's Hospital of Chongqing Medical University, Chongqing 400000, China. Electronic address: [email protected].
  • 4 Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China. Electronic address: [email protected].
  • 5 Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Ningxia 750000, China. Electronic address: [email protected].
  • 6 Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Ningxia 750000, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China. Electronic address: [email protected].
PMID: 41747818 DOI: 10.1016/j.neuroscience.2026.02.033
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords

Cognitive impairment; Exenatide; Neuroinflammation; Neuroprotection; Neurotrophins; Sepsis-induced depression-like behavior.

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