A novel anti-neuroinflammatory pyridylimidazole compound KR-31360.
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.
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.
Jiyeon
J
Ock
Sangseop
S
Kim
Kyu-Yang
KY
Yi
Nak-Jung
NJ
Kim
Hyung Soo
HS
Han
Je-Yoel
JY
Cho
Kyoungho
K
Suk
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000627:therapeutic use; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D015507:Drugs, Investigational / Q000737:chemistry* / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry* / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000737:chemistry* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015507:Drugs, Investigational; D007093:Imidazoles; D018836:Inflammation Mediators; C546458:KR 31360; D011725:Pyridines