Liraglutide alleviates postoperative cognitive impairment in aged mice via NRF2/NLRP3 pathway modulation
Background
Postoperative cognitive dysfunction (POCD) is a common and debilitating complication in elderly surgical patients, significantly impacting quality of life and increasing healthcare costs. Current preventive strategies for POCD are largely ineffective, highlighting an urgent need for novel therapeutic approaches. GLP-1 receptor agonists like liraglutide have demonstrated neuroprotective properties in various neurological conditions, making them a promising candidate for mitigating POCD by targeting underlying mechanisms such as neuroinflammation and oxidative stress.
Study Design
Researchers investigated liraglutide's effect on POCD in aged mice. Mice underwent laparotomy combined with transient superior mesenteric artery occlusion—a model mimicking intestinal ischemia-reperfusion—under sevoflurane anesthesia. Following surgery, mice received liraglutide 300 μg/kg/day for 14 days. Cognitive function was assessed using Y-maze and fear conditioning tests. Microglial activation, synaptic structures, and protein levels were analyzed. Molecular mechanisms focused on the GLP-1R/NRF2 pathway, reactive oxygen species (ROS) accumulation, and NLRP3 inflammasome expression, with an NRF2 inhibitor (ML385) used to confirm pathway involvement.
Results
Liraglutide administration significantly improved behavioral performance in both Y-maze and fear conditioning tests, indicating restored cognitive function. The treatment also notably decreased microglial activation and promoted an M2-like anti-inflammatory phenotype within the brain. Furthermore, liraglutide protected synaptic structures and maintained normal synaptic protein levels. Molecular analysis revealed that liraglutide activated the GLP-1R/NRF2 pathway, leading to a reduction in reactive oxygen species (ROS) accumulation. This activation consequently suppressed the expression of NLRP3 inflammasome components. > The protective effects of liraglutide on cognitive function and neuroinflammation were completely reversed by the NRF2 inhibitor ML385, confirming the critical role of the NRF2 pathway in its mechanism of action.
Key Findings
- Liraglutide improved cognitive performance in aged mice after surgery in Y-maze and fear conditioning tests.
- It decreased microglial activation and promoted an M2-like phenotype, reducing neuroinflammation.
- Liraglutide protected synaptic structures and maintained synaptic protein levels.
- It activated the GLP-1R/NRF2 pathway and reduced reactive oxygen species (ROS) accumulation.
- Liraglutide suppressed NLRP3 inflammasome expression, an effect reversed by the NRF2 inhibitor ML385.
Why It Matters
This study provides compelling evidence that liraglutide could be a viable therapeutic strategy for preventing or treating postoperative cognitive dysfunction in elderly patients. The identified mechanism, involving the NRF2/NLRP3 pathway, offers a novel target for pharmacological intervention. Perioperative administration of liraglutide could potentially improve patient outcomes by reducing neuroinflammation and protecting synaptic integrity after surgery. While preclinical, these findings suggest a clear translational path for repurposing an existing, well-tolerated drug for a significant unmet clinical need, potentially leading to new protocols for high-risk surgical patients.
liraglutide
pocd
postoperative-cognitive-dysfunction
neuroinflammation
nrf2
nlrp3