A Bcr-Abl Inhibitor GNF-2 Attenuates Inflammatory Activation of Glia and Chronic Pain.

Gyun Jee Song,Deepak Prasad Gupta,Taebo Sim,Yong Chul Bae,Jae-Hong Kim,Won-Ha Lee,Sung Hee Park,Sun-Hwa Lee,Mithilesh Kumar Jha,Md Habibur Rahman,In-Kyu Lee,Kyoungho Suk

doi:10.3389/fphar.2019.00543

Abstract

GNF-2 is an allosteric inhibitor of Bcr-Abl. It was developed as a new class of anti-cancer drug to treat resistant chronic myelogenous leukemia. Recent studies suggest that c-Abl inhibition would provide a neuroprotective effect in animal models of Parkinson’s disease as well as in clinical trials. However, the role of c-Abl and effects of GNF-2 in glia-mediated neuroinflammation or pain hypersensitivity has not been investigated. Thus, in the present study, we tested the hypothesis that c-Abl inhibition by GNF-2 may attenuate the inflammatory activation of glia and the ensuing pain behaviors in animal models. Our results show that GNF-2 reduced lipopolysaccharide (LPS)-induced nitric oxide and pro-inflammatory cytokine production in cultured glial cells in a c-Abl-dependent manner. The small interfering ribonucleic acid (siRNA)-mediated knockdown of c-Abl attenuated LPS-induced nuclear factor kappa light chain enhancer of activated B cell (NF-κB) activation and the production of pro-inflammatory mediators in glial cell cultures. Moreover, GNF-2 administration significantly attenuated mechanical and thermal hypersensitivities in experimental models of diabetic and inflammatory pain. Together, our findings suggest the involvement of c-Abl in neuroinflammation and pain pathogenesis and that GNF-2 can be used for the management of chronic pain.

Highlights

Neuroinflammation is highly associated with several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic pain (Katsulov and Mazneikova, 1987; Mosley et al, 2006; Tansey et al, 2007; Calsolaro and Edison, 2016; Chen et al, 2018)
We examined whether c-Abl is involved in the process of inflammatory microglial activation
To investigate the role of c-Abl in inflammatory microglial activation, BV-2 immortalized mouse microglial cell line was stimulated with LPS after GNF-2 pre-treatment (Figure 1A)

Summary

Introduction

Neuroinflammation is highly associated with several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic pain (Katsulov and Mazneikova, 1987; Mosley et al, 2006; Tansey et al, 2007; Calsolaro and Edison, 2016; Chen et al, 2018). The chronic pain pathophysiology is complex and includes peripheral and central neuronal alterations and neuroinflammation. GNF-2 Effects on Chronic Pain [e.g., nitric oxide (NO), cytokines, and chemokines]. This process leads to neuronal death or neurodegeneration (Frank-Cannon et al, 2009; Song and Suk, 2017). In this regard, important clues to the molecular mechanisms of neuropathic pain may be found by closely examining the microglial inflammatory activation and neuroinflammation (Carniglia et al, 2017; Kiguchi et al, 2017; Chen et al, 2018). Studies which target inflammatory mediators may provide novel therapeutic approaches for chronic pain management

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