期刊
FRONTIERS IN PHARMACOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2019.00543
关键词
GNF-2; c-Abl; glia; neuroinflammation; pain
资金
- Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, South Korea [HI16C1501]
- Basic Science Research Program through the National Research Foundation (NRF) - Korean government (MSIT) [2018R1A2A1A05077118, 2016M3C7A1904148, NRF-2017R1A5A2015391]
- NRF [2016R1D1A1B01009186]
- KU-KIST Graduate School of Converging Science and Technology Program
- National Research Foundation of Korea [2018R1A2A1A05077118, 2016R1D1A1B01009186] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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-Abldependent 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 (NE-kappa B) 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.
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