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

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.

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.

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.

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.