A novel small-molecule agonist of PPAR-γ potentiates an anti-inflammatory M2 glial phenotype.
Neuroinflammation is a key process for many neurodegenerative diseases. Activated microglia and astrocytes play an essential role in neuroinflammation by producing nitric oxide (NO), inflammatory cytokines, chemokines, and neurotoxins. Therefore, targeting glia-mediated neuroinflammation using small-molecules is a potential therapeutic strategy. In this study, we performed a phenotypic screen using microglia cell-based assay to identify a hit compound containing N-carbamoylated urethane moiety (SNU-BP), which inhibits lipopolysaccharide (LPS)-induced NO production in microglia. SNU-BP inhibited pro-inflammatory cytokines and inducible nitric oxide synthase in LPS-stimulated microglia, and potentiated interleukin-4-induced arginase-1 expression. PPAR-γ was identified as a molecular target of SNU-BP. The PPAR response element reporter assay revealed that SNU-BP specifically activated PPAR-γ, but not PPAR-δ or -α, confirming that PPAR-γ is the target protein of SNU-BP. The anti-inflammatory effect of SNU-BP was attenuated by genetic and pharmacological inhibition of PPAR-γ. In addition, SNU-BP induced an anti-inflammatory phenotype in astrocytes as well, by inhibiting pro-inflammatory NO and TNF-α, while increasing anti-inflammatory genes, such as arginase-1 and Ym-1. Finally, SNU-BP exhibited an anti-inflammatory effect in the LPS-injected mouse brain, demonstrating a protective potential for neuroinflammatory diseases.
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Gyun Jee
GJ
Song
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Youngpyo
Y
Nam
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Myungjin
M
Jo
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Myungsu
M
Jung
Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
Ja Young
JY
Koo
Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
Wansang
W
Cho
Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
Minseob
M
Koh
Department of Chemistry, Seoul National University, Seoul, Republic of Korea. Electronic address: sbpark@snu.ac.kr.
Seung Bum
SB
Park
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: ksuk@knu.ac.kr.
Kyoungho
K
Suk
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists*; D010641:Phenotype; D051381:Rats; D054852:Small Molecule Libraries / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D047495:PPAR gamma; D054852:Small Molecule Libraries
Anti-inflammatory M2 phenotype; Astrocytes; Microglia; Neuroinflammation; PPAR-γ