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Front Pharmacol. 2019 May 20;10:543. doi: 10.3389/fphar.2019.00543. eCollection 2019.

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

Author information

1
Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung-si, South Korea.
2
Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, South Korea.
3
Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, South Korea.
4
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
5
New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu, and VORONOI Inc., Incheon, South Korea.
6
Department of Internal Medicine, Division of Endocrinology and Metabolism, School of Medicine, Kyungpook National University, Daegu, South Korea.
7
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.
8
Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, South Korea.
9
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, South Korea.
10
BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, South Korea.

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.

KEYWORDS:

GNF-2; c-Abl; glia; neuroinflammation; pain

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