Metformin activates the PI3K/AKT/BDNF axis to attenuate postoperative cognitive dysfunction.

Neuropharmacology

Department of Anesthesiology and Pain Medicine, The Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China. Electronic address:

Published: December 2024

AI Article Synopsis

  • Postoperative cognitive dysfunction (POCD) is a common issue after surgery and anesthesia, and this study investigates how the antidiabetic drug metformin may help improve cognitive function in such cases.
  • The researchers created a mouse model of POCD and discovered that metformin improved cognitive abilities and reduced anxiety, while also enhancing synaptic health in the brain's hippocampus.
  • Metformin works by reducing neuroinflammation and activating the PI3K/AKT signaling pathway, which increases brain-derived neurotrophic factor (BDNF), suggesting it might be a new treatment approach for preventing POCD.

Article Abstract

Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive complication of anesthesia and surgery. Metformin, a widely used antidiabetic drug, has neuroprotective properties and improves cognitive impairment and memory deficits. However, the mechanisms underlying its action in improving cognitive dysfunction after anesthesia and surgery remain unclear. This study aimed to explore the effects of metformin on POCD and the underlying mechanisms at play. We established an in vivo POCD model using isoflurane inhalation anesthesia with exploratory laparotomy. We found that pretreatment with metformin significantly improved cognitive function and anxiety-like behaviors in mice. Additionally, metformin attenuated the impairment of synaptic plasticity induced by POCD and restored levels of synaptic proteins and dendritic density in the hippocampus. Furthermore, metformin attenuated neuroinflammation by downregulating the expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, and reducing neuronal apoptosis. It also activates the PI3K/AKT signaling pathway, resulting in increased expression of brain-derived neurotrophic factor (BDNF). Finally, the PI3K inhibitor, LY294002, reversed the effects of metformin on the levels of PI3K, AKT phosphorylation, and BDNF in vitro cultured HT-22 cells. Additionally, in an in vivo model of POCD, it was observed that cognitive function in mice was significantly suppressed by treatment with the PI3K inhibitor LY294002. These results reveal that metformin may alleviate POCD by modulating the PI3K/AKT/BDNF axis. Our study may provide a novel strategy for preventing and treating POCD with this medication.

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http://dx.doi.org/10.1016/j.neuropharm.2024.110262DOI Listing

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