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

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

Brain Behav Immun Health. 2020 May 21:5:100083. doi: 10.1016/j.bbih.2020.100083. eCollection 2020 May.

Authors

Sheelu Monga¹, Nunzio Denora², Valentino Laquintana², Massimo Franco², Ilan Marek³, Sukhdev Singh³, Rafi Nagler¹, Abraham Weizman^{4

5}, Moshe Gavish¹

Affiliations

¹ Technion- Israel Institute of Technology, Ruth and Bruce Rappaport Faculty of Medicine, Israel.
² Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Italy.
³ Technion- Israel Institute of Technology, Schulich Faculty of Chemistry, Israel.
⁴ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁵ Research Unit, Geha Mental Health Center and Felsenstein Medical Research Center, Petah Tikva, Israel.

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.

Keywords: 2,4-Di-Cl-MGV-1; BV-2 cell line; LPS (Lipopolysaccharide); M1 and M2 pathway; Microglial activation; Neuroinflammation; Pro-inflammatory cytokines; Translocator protein (TSPO).