Identification of KT-15073 as an inhibitor of lipopolysaccharide-induced microglial activation.

Abstract:

:Neuroinflammation has recently been implicated as an important mechanism responsible for the progression of neurodegenerative diseases. Activated microglia produce various proinflammatory cytokines and nitric oxide (NO) that are toxic to neurons. Thus, inhibition of microglial activation may alleviate neuroinflammatory and neurodegenerative processes. Among several fluorovinyloxyacetamide derivatives that were screened by microglia cell-based assay, a novel synthetic compound KT-15073 was identified to strongly attenuate the microglial production of NO and tumor necrosis factor-alpha (TNF-alpha). This compound also suppressed the gene expression of interleukin-1beta, inducible nitric oxide synthase, and TNF-alpha. KT-15073 inhibited the nuclear translocation and DNA binding of nuclear factor-kappaB as well as phosphorylation of p38 mitogen-activated protein kinase. In addition, KT-15073 reduced the cytotoxicity of lipopolysaccharide (LPS)-stimulated microglia toward B35 neuroblastoma cells in the microglia/neuroblastoma coculture, suggesting that the compound might exhibit the neuroprotective activity. Thus, KT-15073 has an anti-inflammatory activity in microglia, and may have a therapeutic potential for the treatment of neuroinflammatory or neurodegenerative diseases.

journal_name

Biol Pharm Bull

authors

Ock J,Hong SH,Suk K

doi

10.1248/bpb.33.461

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

461-7

issue

3

eissn

0918-6158

issn

1347-5215

pii

JST.JSTAGE/bpb/33.461

journal_volume

33

pub_type

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