The protective effect of the TSPO ligands 2,4-Di-Cl-MGV-1, CB86, and CB204 against LPS-induced M1 pro-inflammatory activation of microglia

Sheelu Monga,Nunzio Denora,Valentino Laquintana,Massimo Franco,Ilan Marek,Sukhdev Singh,Rafi Nagler,Abraham Weizman,Moshe Gavish

doi:10.1016/j.bbih.2020.100083

Abstract

We have shown previously, that the 18 kDa translocator protein (TSPO) synthetic ligands quinazoline derivatives (2-Cl-MGV-1 and MGV-1) can inhibit activation of in BV-2 microglial cells. In the present study we assessed the impact of novel TSPO ligands on lipopolysaccharide (LPS)-induced microglial activation as expressed by release of pro-inflammatory molecules, including cytokines [interleukin-6 (IL-6), IL-1β, interferon- γ (IFN-γ)] nitric oxide (NO), CD8, and cyclo-oxygenase-2 (COX-2). The TSPO ligands 2,4-Di-Cl-MGV-1, CB86, and CB204 counteracted with the LPS-induced microglial activation. Exposure to LPS along with the TSPO ligand 2,4-Di-Cl-MGV-1 (25 μM) reduced significantly the release of NO by 24-, IL-6 by 14-, IL-β by 14-, IFN- γ by 6-, and TNF-α by 29-folds, respectively. In contrast to the anti-neuroinflammatory effect of the TSPO ligands, the effect of diclofenac sodium (DS; 25 μM) did not reach statistical significance. No alterations in IL-10 and IL-13 were detected (M2 anti-inflammatory pathway) during the inhibition of M1 pro-inflammatory pathway.

Highlights

Ligands active at the 18 kDa Translocator Protein (TSPO) exhibit immunomodulatory effects (Monga et al, 2019)
We have shown that the TSPO ligands 2-Cl-MGV-1 and MGV-1 counteract with microglial activation including the release of pro-inflammatory cytokines (Monga et al, 2019)
Our current study shows that the TSPO ligands 2,4-DiCl-MGV-1 and CB86 are efficacious in attenuating the activation of microglia and the corresponding release of pro-inflammatory cytokines

Summary

Introduction

Ligands active at the 18 kDa Translocator Protein (TSPO) exhibit immunomodulatory effects (Monga et al, 2019). We have shown that the synthetic TSPO ligands 2-Cl-MGV-1 and MGV-1 appear to have beneficial effects in prevention of cell death and inflammatory processes in BV-2, a murine microglial cell line (Monga et al, 2019). We analyzed the immunomodulatory properties of this ligand in BV-2 cell line. We have used another two TSPO ligands CB86 and CB204 (Denora et al, 2017; Iacobazzi et al, 2017)

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