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

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

doi:10.3389/fphar.2019.00543

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

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

Authors

Gyun Jee Song^{1

2}, Md Habibur Rahman³, Mithilesh Kumar Jha^{3

4}, Deepak Prasad Gupta^{1

3}, Sung Hee Park¹, Jae-Hong Kim³, Sun-Hwa Lee⁵, In-Kyu Lee⁶, Taebo Sim^{7

8}, Yong Chul Bae⁹, Won-Ha Lee¹⁰, Kyoungho Suk³

Affiliations

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.