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

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4 Citations (Scopus)

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.

Original languageEnglish
Article number543
JournalFrontiers in Pharmacology
Volume10
Issue numberMAY
DOIs
Publication statusPublished - 2019

Keywords

  • C-Abl
  • GNF-2
  • Glia
  • Neuroinflammation
  • Pain

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Song, G. J., Rahman, M. H., Jha, M. K., Gupta, D. P., Park, S. H., Kim, J. H., Lee, S. H., Lee, I. K., Sim, T., Bae, Y. C., Lee, W. H., & Suk, K. (2019). A BCR-ABL inhibitor GNF-2 attenuates inflammatory activation of glia and chronic pain. Frontiers in Pharmacology, 10(MAY), [543]. https://doi.org/10.3389/fphar.2019.00543