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Anti-Inflammatory Effect of KW-2449 on Autoimmune Encephalomyelitis: An Experimental Study on Mice
Hasan N Ahmadabad1, Allireza Abbaspour1, Yaser Panahi1
1Department of Pathobiology and Laboratory Sciences, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
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.
Insights
KW-2449, a novel multikinase inhibitor, significantly reduced the clinical signs and inflammatory markers in a mouse model of multiple sclerosis (MS). This study demonstrates KW-2449
Area of Science:
- Neuroimmunology
- Pharmacology
- Molecular Biology
Background:
- The multikinase inhibitor KW-2449 targets FLT3, ABL, ABL-T315I, and Aurora A.
- FLT3 and Aurora A kinases are implicated in the pathogenesis of multiple sclerosis (MS).
- The immunomodulatory effects of KW-2449 in experimental autoimmune encephalomyelitis (EAE), an MS model, remain uninvestigated.
Purpose of the Study:
- To investigate the therapeutic effects of KW-2449 on the EAE mouse model.
- To evaluate the impact of KW-2449 on inflammatory markers and neuropathology in EAE.
Main Methods:
- C57BL/6 mice with EAE were orally administered KW-2449 (10 mg/kg/day).
- Histological analysis of brain and cerebellum assessed pathological scores.
- Quantitative real-time PCR (qRT-PCR) and ELISA measured gene and serum levels of TNF-α, IL-6, CCL2, and MMP-2.
Main Results:
- KW-2449 treatment significantly reduced clinical scores, inflammatory cell infiltration, and demyelination in EAE mice.
- KW-2449 administration led to decreased expression and serum levels of pro-inflammatory cytokines (TNF-α, IL-6, CCL2) and MMP-2.
Conclusions:
- KW-2449, as a multikinase inhibitor, effectively modulates inflammatory cytokine cascades in both the brain and plasma.
- KW-2449 demonstrates potential in reducing the manifestations of EAE pathogenesis.
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