Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug

Autor: Kyoung Soo Kim, Snigdha Samarpita, Joo Young Kim, Mahaboobkhan Rasool
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
musculoskeletal diseases
medicine.medical_specialty
lcsh:Diseases of the musculoskeletal system
Poly(I:C)
Arthritis
Lipopolysaccharide (LPS)
Pharmacology
Pathogenesis
Arthritis
Rheumatoid
03 medical and health sciences
0302 clinical medicine
Damage-associated molecular patterns (DAMPs)
Internal medicine
medicine
Animals
Humans
Rats
Wistar
Receptor
Cells
Cultured
TAK-242 (resatorvid)
Toll-like receptor
Sulfonamides
Fibroblast-like synoviocytes (FLS)
business.industry
TLR4 inhibitor
medicine.disease
Arthritis
Experimental
Synoviocytes
Rheumatology
Rats
Toll-Like Receptor 4
030104 developmental biology
Rheumatoid arthritis
Antirheumatic Agents
Rheumatoid arthritis (RA)
TLR3
TLR4
Adjuvant-induced arthritis (AIA) rat model
Female
lcsh:RC925-935
business
030217 neurology & neurosurgery
Research Article
Zdroj: Arthritis Research & Therapy, Vol 22, Iss 1, Pp 1-10 (2020)
Arthritis Research & Therapy
ISSN: 1478-6362
Popis: Background Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis. Methods The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model. Results TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1β-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR. Conclusions Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.
Databáze: OpenAIRE
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