The TSPO Ligands 2-Cl-MGV-1, MGV-1, and PK11195 Differentially Suppress the Inflammatory Response of BV-2 Microglial Cell to LPS.

Maya Azrad,Leo Veenman,Moshe Gavish,Abraham Weizman,Nidal Zeineh

doi:10.3390/ijms20030594

Abstract

The 18 kDa Translocator Protein (TSPO) is a marker for microglial activation as its expression is enhanced in activated microglia during neuroinflammation. TSPO ligands can attenuate neuroinflammation and neurotoxicity. In the present study, we examined the efficacy of new TSPO ligands designed by our laboratory, MGV-1 and 2-Cl-MGV-1, in mitigating an in vitro neuroinflammatory process compared to the classic TSPO ligand, PK 11195. We exposed BV-2 microglial cells to lipopolysaccharide (LPS) for 24 h to induce inflammatory response and added the three TSPO ligands: (1) one hour before LPS treatment (pretreatment), (2) simultaneously with LPS (cotreatment), and (3) one hour after LPS exposure (post-treatment). We evaluated the capability of TSPO ligands to reduce the levels of three glial inflammatory markers: cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO). We compared the effects of the two novel ligands to PK 11195. Both 2-Cl-MGV-1 and MGV-1 reduced the levels of glial COX-2, iNOS, and NO in LPS-treated BV-2 cells more efficiently than PK 11195. Notably, even when added after exposure to LPS, all ligands were able to suppress the inflammatory response. Due to their pronounced anti-inflammatory activity, 2-Cl-MGV-1 and MGV-1 may serve as potential therapeutics in neuroinflammatory and neurodegenerative diseases.

Highlights

Neuroinflammation is implicated in the pathophysiology of various brain diseases and brain injuries, and is associated with a broad range of neuroimmune responses
We examined the efficacy of two new Translocator Protein (TSPO) ligands, 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2-Cl-MGV-1) and 2-phenylquinazolin-4-yl dimethylcarbamate (MGV-1) [22], designed by our laboratory, in diminishing neuroinflammation in comparison to the classic TSPO ligand, PK 11195
Pretreatment with PK 11195 one hour prior to LPS treatment resulted in reduction of COX-2 levels by 59% (Bonferroni p < 0.001), while pretreatment with 2-Cl-MGV-1 and MGV-1 reduced COX-2 levels by 89% and 76%, respectively, compared to LPS-treated cells (Bonferroni p < 0.001 for both)

Summary

Introduction

Neuroinflammation is implicated in the pathophysiology of various brain diseases and brain injuries, and is associated with a broad range of neuroimmune responses. Such responses typically involve the blood–brain barrier (BBB), glial cells, and neurons [1]. Exaggerated response is often accompanied by disruption of the BBB and neuronal damage due to the microglial neurotoxic activity [2]. It is not surprising that chronic neuroinflammation and microglial activation are associated with various neurodegenerative diseases, such as encephalitis [8], Alzheimer’s disease [9,10,11], Parkinson’s disease [12], multiple sclerosis (MS) [13], and amyotrophic lateral sclerosis (ALS) [14]

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