title: A novel compound VSC2 has anti-inflammatory and antioxidant properties in microglia and in Parkinson's disease animal model.
abstract: OBJECTIVE
  Neuroinflammation through microglial activation is involved in the pathogenesis of neurodegenerative diseases including Parkinson's disease (PD), a major neurodegenerative disorder characterized by dopaminergic neuronal death in the substantia nigra. We examined our novel synthetic compound VSC2 for its anti-inflammatory properties towards development of a PD therapy.
  
  
  METHODS
  We tested the effects of VSC2 on production of various NF-κB-dependent proinflammatory molecules and Nrf2-dependent antioxidant enzymes in BV-2 microglia and in vivo.
  
  
  RESULTS
  The vinyl sulfone compound, VSC2, most effectively suppressed the production of NO in LPS-activated microglia. It also down-regulated expression of inducible NOS (iNOS), COX-2, IL-1β and TNF-α and inhibited nuclear translocalization and transcriptional activity of NF-κB. VSC2 increased total and nuclear Nrf2 levels, induced Nrf2 transcriptional activity and was bound to Keap1 with high affinity. Expression of the Nrf2-regulated antioxidant enzyme genes NAD(P)H quinone oxidoreducase-1 (NQO-1), haem oxygenase-1 (HO-1) and glutamylcysteine ligase (GCL) were up-regulated by VSC2. In the MPTP mouse model of PD, oral administration of VSC2 decreased the number of activated microglia in the substantia nigra, lowered the levels of iNOS, COX-2 and IL-1β, and protected the dopaminergic neurons. VSC2 also elevated the levels of NQO1, HO-1, GCL and Nrf2 in the nigrostriatal area.
  
  
  CONCLUSIONS
  VSC2 has both anti-inflammatory and antioxidant properties and prevented neuroinflammation in microglia and in an animal model of PD. This suggests VSC2 as a potential candidate for PD therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Ji Ae
authors.initials: JA
authors.lastname: Lee
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Woo
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.forename: Se Hee
authors.initials: SH
authors.lastname: Han
authors.forename: Bo Ko
authors.initials: BK
authors.lastname: Jang
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Choi
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014753:Vinyl Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000601550:1-(2-((2-methoxyphenyl)sulfonyl)vinyl)-2-chlorobenzene; D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D014753:Vinyl Compounds; D009569:Nitric Oxide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine