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

Abstract

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.

CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

“…In addition, Tatsumi et al suggest that ROCK activation is necessary for P38 MAPK phosphorylation in the development of chronic pain [31]. Furthermore, it was also reported by Wilkerson et al that AM1241 produced profound anti-allodynia with a corresponding decrease in phosphorylation of p38MAPK immunoreactive cells and their protein levels in nonneuropathic pain rats [34]. Intrathecal injection of the p38MAPK antagonist SB203580 decreased NF-κB, resulting 20 in pain relief in neuropathic pain rats [11,36].…”

“…More recent studies convince that miR-124 is one of the most abundant microRNAs in the brain and spinal cord that regulates microglial function[17,18,34,35]. The decreased expression of miR-124 was reported in cancer pain, carrageenan-induced and peripheral nerve injury-induced chronic As shown inFig.6A, treatment with AM1241 reduced this CCI-induced mechanical allodynia (P<0.05, compare with CCI rats) and the effect was reversed by the AM630 (P<0.05, compare with AM1241-treated CCI rats).…”

Circ_0002984 induces proliferation, migration and inflammation response of VSMCs induced by ox‐LDL through miR‑326‐3p/VAMP3 axis in atherosclerosis

“… 28 VAMP3 is a crucial therapeutic target for microglial activation by surgical trauma. 29 VAMP3 is involved in endothelial weibel‐palade bodies in exocytosis. 30 VAMP3 mediates the disturbed secretion of flow‐induced endothelial microRNAs.…”

Peritumoral Microenvironment in High-Grade Gliomas: From FLAIRectomy to Microglia–Glioma Cross-Talk

“…Karthikeyan et al demonstrated how microglial cells exposed to GBM conditioned-medium exhibited a greater ability to migrate and attributed this phenotype to decreased levels of miR-146a and resulting upregulation of its target SMAD family member 4 (SMAD4), a critical node involved in the activation of the TGF-β pathway and genes such as matrix metallopeptidase 9 (MMP9), which facilitates tumor cell invasion [81]. A reverse cross-talk, between miR-124-3p-containing microglial exosomes and neuronal cells, was demonstrated by Li et al in a mouse model of brain injury [82]; this brain-specific miRNA is downregulated both in activated microglia and in GBM cells [43,83,84]. Li et al demonstrated that temozolomide (TMZ)-resistant GBM cells trigger the M2-polarization of microglial cells thanks to the long-noncoding RNA SNHG15 (upregulated in GBM cells), and its associated molecular axis made up of miR-627 (tumor suppressor, normally downregulated in GBM) and CDK6 (oncoprotein, directly targeted by miR-627) [85].…”