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

Authors
Song, Gyun JeeRahman, Md HabiburJha, Mithilesh KumarGupta, Deepak PrasadPark, Sung HeeKim, Jae-HongLee, Sun-HwaLee, In-KyuSim, TaeboBae, Yong ChulLee, Won-HaSuk, Kyoungho
Issue Date
2019-05
Publisher
FRONTIERS MEDIA SA
Citation
FRONTIERS IN PHARMACOLOGY, v.10
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-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.
Keywords
C-ABL; OXIDATIVE STRESS; TYROSINE KINASE; MICROGLIAL ACTIVATION; PARKINSONS-DISEASE; PIVOTAL ROLE; NEUROINFLAMMATION; PHOSPHORYLATION; SYNUCLEIN; PATHOGENESIS; GNF-2; c-Abl; glia; neuroinflammation; pain
ISSN
1663-9812
URI
https://pubs.kist.re.kr/handle/201004/120020
DOI
10.3389/fphar.2019.00543
Appears in Collections:
KIST Article > 2019
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