Induction of M1 polarization in BV2 cells by propofol intervention promotes perioperative neurocognitive disorders through the NGF/CREB signaling pathway: an experimental research

Nerve growth factor (NGF) is critical in regulating the homeostasis of microglial cells. It activates various signaling pathways that mediate the phosphorylation of cAMP response element-binding protein (CREB) at key regulatory sites. The decrease in phosphorylated CREB (p-CREB) expression is linked to neuroinflammatory responses. The exact molecular mechanism by which propofol regulates microglial polarization and induces neuroinflammation via the NGF/CREB signaling axis remains unclear. This study aims to investigate the specific mechanisms by which propofol induces perioperative neurocognitive disorders through microglial M1 polarization and neuroinflammation via the NGF/CREB signaling pathway. We demonstrated that propofol impairs neurocognitive function in mice, as evidenced by behavioral deficits. It reduces NGF expression in hippocampal microglia and BV2 cells, where protein-protein interactions between NGF and CREB suggest that NGF primarily regulates neurocognitive function by modulating p-CREB. Propofol intervention and inhibition of the NGF/CREB pathway promote M1 polarization in hippocampal microglia and BV2 cells, leading to reduced cell proliferation, increased apoptosis, elevated oxidative stress, and higher levels of the inflammatory marker TNF-α. Exogenous NGF does not alter the expression of NGF or total CREB but significantly upregulates p-CREB, indicating its regulatory role in signaling pathways associated with microglial activation. Moreover, exogenous NGF mitigates propofol-induced cognitive impairments and M1 polarization, reducing apoptosis and oxidative stress levels. Our findings suggest that propofol downregulates the expression of NGF and CREB, subsequently reducing p-CREB levels. This downregulation induces M1 polarization of microglia, promoting the progression of neuroinflammation and contributing to the development of perioperative neurocognitive disorders.