Semaglutide significantly reduced brain infarct size and neuroinflammation in a mouse model of perioperative stroke by boosting a newly identified protective subset of brain immune cells (Spp1+ microglia/macrophages) that express GLP-1 receptors.
Novel protective cell subset identifiedSingle-cell sequencing discovered Spp1+ microglia/macrophages with anti-inflammatory properties and GLP-1 receptors — a previously unknown cell population that semaglutide can expand to protect the brain after perioperative stroke.
What the researchers found
Single-cell RNA sequencing in a perioperative ischemic stroke (PIS) mouse model identified a novel Spp1+ macrophage/microglia subgroup with enriched anti-inflammatory pathways and distinct lipid metabolic reprogramming. These cells express GLP-1 receptors, confirmed by immunofluorescence.
Semaglutide treatment resulted in:
- Significant reduction in cerebral infarct volume in PIS mice compared to ischemic stroke alone
- Increased proportion of Spp1+Edu+Iba-1+ cells (proliferating protective microglia) at 3 days post-PIS
- Significant attenuation of neuroinflammatory markers
- Significant improvement in sensorimotor function within 3 days
These findings reveal a novel protective immune cell subset and demonstrate it can be therapeutically expanded by semaglutide.
Why it matters
Perioperative stroke is a feared surgical complication with limited treatment options. Surgery itself worsens stroke outcomes through neuroinflammation, creating a worse situation than a stroke happening outside the surgical context. This study identifies both a new protective immune mechanism and a way to enhance it with an existing drug. If semaglutide can reduce perioperative stroke damage, it could benefit the millions of patients who undergo surgery and are at risk for this complication.
How the study worked
Researchers used a perioperative ischemic stroke mouse model combining surgery with brain ischemia. Single-cell RNA sequencing was used to characterize immune cell populations in the ischemic brain. GLP-1 receptor expression on Spp1+ cells was confirmed by immunofluorescence. Semaglutide was administered intraperitoneally. Outcomes were assessed using infarct volume measurement, high-parameter flow cytometry, immunofluorescence staining, RNA sequencing, and sensorimotor behavioral testing.
What this study cannot tell us
This is a preclinical study in mice that may not translate directly to human perioperative stroke. The perioperative stroke model combines surgery with experimental ischemia, which may differ from how strokes actually occur in surgical patients. Semaglutide was given as prevention/early treatment — its effectiveness when given after stroke onset is unknown. The 3-day follow-up is short and doesn't assess long-term outcomes. Specific semaglutide doses used may not correspond to human clinical doses.
How to read the evidence
This is a methodologically rigorous preclinical study using state-of-the-art single-cell RNA sequencing to identify novel mechanisms. Published in Journal of Neuroinflammation, it provides strong mechanistic evidence but all findings are from mouse models.
When this study was published
Published in 2025, this is cutting-edge research using advanced single-cell genomics to understand GLP-1 agonist neuroprotection at the cellular level.
The bigger picture
This study adds perioperative neuroprotection to semaglutide's expanding portfolio of effects beyond metabolic disease. The identification of GLP-1 receptors on a specific neuroprotective immune cell subset provides a clear mechanistic link for how GLP-1 drugs protect the brain. This kind of immune-modulatory neuroprotection could have implications beyond perioperative stroke — potentially for traumatic brain injury, neurodegeneration, and other conditions involving neuroinflammation.
Questions still open
- Could pre-operative semaglutide administration reduce perioperative stroke risk in high-risk surgical patients?
- Does the Spp1+ microglia/macrophage protective mechanism also apply to non-perioperative strokes?
- Are diabetic patients already on semaglutide at lower risk for perioperative neurological complications?
Common questions
How does semaglutide protect the brain during surgery-related stroke?
Why are strokes during surgery more dangerous than other strokes?
Read the original research
Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke.
Journal of neuroinflammation, 22(1), 143
Citation
Li, Yan; Fan, Qiuyue; Pang, Rui; Cai, Ling; Qi, Jie; Chen, Weijie; Zhang, Yueman; Chen, Chen; Yu, Weifeng; Li, Peiying. (2025). Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke.. Journal of neuroinflammation, 22(1), 143. https://doi.org/10.1186/s12974-025-03465-9