TSPO Ligands PK11195 and Midazolam Reduce NLRP3 Inflammasome Activation and Proinflammatory Cytokine Release in BV-2 Cells

Abstract

Neuroinflammation related to microglial activation plays an important role in neurodegenerative diseases. Translocator protein 18 kDa (TSPO), a biomarker of reactive gliosis, its ligands can reduce neuroinflammation and can be used to treat neurodegenerative diseases. Therefore, we explored whether TSPO ligands exert an anti-inflammatory effect by affecting the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, thereby inhibiting the release of inflammatory cytokines in microglial cells. In the present study, BV-2 cells were exposed to lipopolysaccharide (LPS) for 6 h to induce an inflammatory response. We found that the levels of reactive oxygen species (ROS), NLRP3 inflammasome, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were significantly increased. However, pretreatment with TSPO ligands inhibited BV-2 microglial and NLRP3 inflammasome activation and significantly reduced the levels of ROS, IL-1β, and IL-18. Furthermore, a combination of LPS and ATP was used to activate the NLRP3 inflammasome. Both pretreatment and post-treatment with TSPO ligand can downregulate the activation of NLRP3 inflammasome and IL-1β expression. Finally, we found that TSPO was involved in the regulation of NLRP3 inflammasome with TSPO ligands treatment in TSPO knockdown BV2 cells. Collectively, these results indicate that TSPO ligands are promising targets to control microglial reactivity and neuroinflammatory diseases.

TSPO Ligands Protect against Neuronal Damage Mediated by LPS-Induced BV-2 Microglia Activation

“…Our previous studies have shown that TSPO ligands PK11195 and Midazolam have potential therapeutic effects on neuroinflammation [ 21 ]. In the current study, we investigate the antineuroinflammatory effects and possible mechanisms of PK11195 and Midazolam in LPS-activated BV-2 microglia cells in vitro .…”

Efficacy of TSPO ligands on neuronal damage mediated by LPS-stimulated BV-2 microglial activation

“…Researches over the last few decades have had a strong emphasis on the interaction of TSPO with its ligands, the most common of which is PK11195 12 .TSPO ligands have shown promising therapeutic prospects in various studies [14][15] . Previous studied in our laboratory showed PK11195 and Midazolam have anti-in ammatory action in vitro 21 . Meanwhile, in vivo we found that PK11195 could regulate the process of mitophagy 23 .…”

“…Our previous studies have shown that TSPO ligands have potential therapeutic effects on neuroin ammation 21 . In the current study, we go ahead to investigate the anti-neuroin ammatory effects and possible mechanisms of TSPO ligands in LPS-activated BV-2 microglial cells in vitro.…”

Continuous midazolam infusion can minimize the pro-inflammatory response to anesthesia and surgery for pediatric patients with intra-abdominal infection: Comparative study versus continuous propofol infusion

“…Thereafter, Lu et al [26] showed that midazolam can significantly inhibit IL-1β-induced release of IL-6 in rat C6 glioma cells in a concentration-dependent fashion up to inhibition by 43.58% with 3 μM midazolam concentration, while propofol elicited no significant effect on IL-1β-induced the release of IL-6. Recently, Horiguchi et al [34] and Feng et al [35] experimentally reported that midazolam pretreatment suppressed LPS-induced the upregulation of the costimulatory molecule CD80 and the release of IL-6 and NO in peripheral monocyte-derived macrophages with the suppression of the activation of NF-κB and mitogenactivated protein kinase in human cells.…”