Inhibition of STAT3 phosphorylation attenuates perioperative neurocognitive disorders in mice with D-galactose-induced aging by regulating pro-inflammatory reactive astrocytes

Background: Perioperative Neurocognitive Disorders (PND) are associated withanesthesia and surgery, especially in the elderly. Astrocyte activation in old mice correlates with PND development. These cells can switch to a pro-inflammatory or an anti-inflammatory phenotype, regulated by the STAT3 pathway. It remains unclear whether STAT3 can alleviate PND symptoms in elderly mice by modulating the transitions between these astrocyte phenotypes.

Methods: Senescence was induced in eight-week-old male C57BL/6J mice with D-galactose, followed by tibial fracture surgery under anesthesia to model PND. On the third postoperative day, cognitive function was assessed using fear conditioning, synaptic plasticity using Golgi/ electrophysiology, and astrocyte phenotype /STAT3/pSTAT3(phosphorylated STAT3) using Western blot/immunofluorescence. The content of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), was also measured. Primary astrocytes were stimulated with the conditioned medium referred to as ACM to induce pro-inflammatory reactive astrocytes. Stattic, an inhibitor of STAT3 phosphorylation, was used to investigate its effects on astrocyte phenotypic transformation and hippocampus-dependent learning and memory in aging mice, both in vitro and in vivo.

Results: On the third postoperative day, pSTAT3 levels and pro-inflammatory astrocytes increased in the hippocampal CA1 region, with no change in total STAT3 or anti-inflammatory astrocytes, accompanied by a decrease in GDNF and BDNF.ACM treatment of primary astrocytes promoted pro-inflammatory phenotype conversion, which was inhibited by stattic without affecting anti-inflammatory phenotype. Intraperitoneal injection of stattic in mice reduced the accumulation of pro-inflammatory astrocytes, increased the levels of BDNF and GDNF, enhanced synaptic plasticity, and improved hippocampus-dependent learning and memory functions in anesthesia-induced senescent mice, without altering anti-inflammatory astrocytes.

Conclusions: Inhibiting STAT3 phosphorylation may improve synaptic plasticity in the CA1 region of the hippocampus by modulating pro-inflammatory astrocytes, thereby alleviating perioperative neurocognitive dysfunction in D-galactose-induced aging mice.