IL-12p70 Induces Neuroprotection via the PI3K-AKT-BCL2 Axis to Mediate the Therapeutic Effect of Electroacupuncture on Postoperative Cognitive Dysfunction.

Abstract

Postoperative cognitive dysfunction (POCD), a postsurgical decline in cognitive function, primarily affects older adults and worsens their prognosis. Although elevated interleukin-12p70 (IL-12p70) is closely correlated with slower cognitive decline in older adults, its role in POCD remains unclear. Here, IL-12p70 is identified as a significant mediator of therapeutic effect of electroacupuncture (EA) on POCD. EA at acupoints ST36, GV20, and GV24 significantly enhanced cognitive behaviors of POCD mice. IL-12p70, downregulated in POCD mice but rescued by EA treatment, is the cytokine closely associated with EA's therapeutic effect. Clinically, IL-12p70 is downregulated in older adults' serum post-surgery. Furthermore, IL-12p70 exerts a potent neuroprotective effect in both neuronal cell lines and primary hippocampal neurons. The PI3K-AKT-BCL2 axis enriched by in silico analysis is validated as the signaling mechanism underlying IL-12p70-induced neuroprotection. In vivo, beneficial effects of EA treatment on the activation of PI3K-AKT-BCL2 axis and POCD are reproduced by IL-12p70 administration but attenuated by IL-12p70 knockdown. The findings reveal a novel mechanism underlying the therapeutic effect of EA on POCD, demonstrating that IL-12p70 exerts a neuroprotective effect by activating PI3K-AKT-BCL2 axis in hippocampal neurons. The newly-discovered function and mechanism of IL-12p70 highlight its potential in treating cognitive disorders.