Title:Anti-Inflammatory Effect of KW-2449 on Autoimmune Encephalomyelitis: An Experimental Study on Mice
Volume: 21
Issue: 9
Author(s): Hasan N. Ahmadabad, Allireza Abbaspour, Yaser Panahi, Saeed Tahmasebi, Nikoo Hossein-Khannazer, Sanaz Afraei*, Hosein Miladi, Mahdi Goudarzvand, Ali N. Kamali, Yasser Bagheri, Reza Yazdani, Maria M. Di Fiore and Gholamreza Azizi*
Affiliation:
- Department of Cell and Molecular Biology, University of Tehran, Tehran,Iran
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj,Iran
Keywords:
Experimental autoimmune encephalomyelitis, KW-2449, Multiple sclerosis, TNF-α, IL-6, CCL-2, MMP-2.
Abstract:
Background: The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL,
ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis
of multiple sclerosis (MS). KW-2449 could modulate immune cells, but the immunomodulatory effects
of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated
yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model.
Methods: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution
and compared with EAE and control mice. Following the treatment, histological analyses
were performed on the brain and cerebellum to evaluate the pathological score. The gene expression
levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif)
ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and
MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA).
Results: The results indicated that the clinical score, the infiltration of inflammatory cells and the
demyelination in EAE mice treated with KW-2449 decreased significantly compared to control
groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines, and MMP-2 in
both brain mRNA expressions and serum levels of EAE mice.
Conclusion: The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses
of cytokine cascades either in the brain or in plasma and reduces EAE pathogenesis manifestation.
