Linked Life Data

19800321

Source:http://linkedlifedata.com/resource/pubmed/id/19800321

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2009-12-16
pubmed:abstractText
Excessive microglial activation with overexpression of proinflammatory cytokines and oxidative stress products is linked to the progression of several neurodegenerative diseases; therefore, suppression of microglial activation is a potential therapeutic approach against these diseases. Since nitric oxide (NO) is one of the major inflammatory mediators that are produced by activated microglia, inhibitory effects of novel synthetic compounds on microglial NO production were investigated. From the mouse microglia cell-based assays, an imidazo [4,5-b] pyridine compound KR-31360 was identified as an inhibitor of microglial NO production with an IC(50) value of 2 microM. Structure-activity relationship study indicated that 5-position of imidazo [4,5-b] pyridine ring is critical for the activity. KR-31360 also inhibited lipopolysaccharide (LPS)-induced secretion of tumor necrosis factor alpha (TNF-alpha) and transcription of TNF-alpha, interleukin-1 beta, and inducible nitric oxide synthase as well as activation of nuclear factor kappa B and mitogen-activated protein kinases. KR-31360 was neuroprotective by suppressing microglial neurotoxicity in a microglia-neuron coculture. The neuroprotective activity of the compound was most effective when microglia were pretreated with the compound prior to LPS challenge. The inhibitory effect of KR-31360 on microglial activation was further demonstrated in a mouse neuroinflammation model in vivo: compared to vehicle-injected animals, KR-31360 injection attenuated LPS-induced microglial activation as evidenced by isolectin B4 staining and proinflammatory gene expression of brain sections. DNA microarray analysis supported that KR-31360 targeted Toll-like receptor 4 pathways. In addition to being a new drug candidate against neuroinflammatory diseases, the compound may be a powerful tool for the better understanding of microglia biology and neuroinflammation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1873-2968
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
79
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
596-609
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
A novel anti-neuroinflammatory pyridylimidazole compound KR-31360.
pubmed:affiliation
Department of Pharmacology, School of Medicine, Brain Science and Engineering Institute, CMRI, Kyungpook National University, 101 Dong-In, Joong-gu, Daegu 700-422, Republic of Korea.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't