miR-124/VAMP3 is a novel therapeutic target for mitigation of surgical trauma-induced microglial activation

Activation of microglia and the subsequently elevated inflammatory cytokine release in the brain during surgery predispose individuals to cognitive dysfunction,also known as postoperative cognitive dysfunction(POCD).miR-124 is one of the most abundant microRNAs in the brain that regulates microglial function.Elucidating the role of miR-124 in microglial activation in the context of surgery may therefore promote understanding of as well as therapeutic development for post-surgical disorders involving microglial activation.The downstream targets of miR-124 were investigated using bioinformatic screening and dual-luciferase reporter assay validation,and vesicle-associated membrane protein 3(VAMP3)was identified as a potential target.The kinetics of miR-124/VAMP3 expression was first examined in vitro in microglial cells(primary microglia and BV2 microglial cells)following lipopolysaccharide(LPS)stimulation.LPS induced a time-dependent decrease of miR-124 and upregulated the expression of VAMP3.Manipulating miR-124/VAMP3 expression by using miR-124 mimics or VAMP3-specific siRNA in LPS-stimulated BV2 microglial cells inhibited BV2 microglial activation-associated inflammatory cytokine release.To further examine the role of miR-124/VAMP3 in a surgical setting,we employed a rat surgical trauma model.Significant microglial activation and altered miR-124/VAMP3 expression were observed following surgical trauma.We also altered miR-124/VAMP3 expression in the rat surgical trauma model by administration of exogenous miR-124 and by using electroacupuncture,which is a clinically applicable treatment that modulates microglial function and minimizes postoperative disorders.We determined that electroacupuncture treatment specifically increases the expression of miR-124 in the hypothalamus and hippocampus.Increased miR-124 expression with a concomitant decrease in VAMP3 expression resulted in decreased inflammatory cytokine release related to microglial activation post-surgery.Our study indicates that miR-124/VAMP3 is involved in surgery-induced microglial activation and that targeting miR-124/VAMP3 could be a potential therapeutic strategy for postoperative disorders involving microglial activation.