title: Modulation of inflammatory signaling and cytokine release from microglia by celastrol incorporated into dendrimer nanocarriers.
abstract: OBJECTIVE
  This study investigates the capacity of a potent anti-inflammatory nanomedicine, celastrol, incorporated into poly(amidoamine) dendrimers, to inhibit endotoxin-mediated signaling in microglia.
  
  
  METHODS
  Celastrol was incorporated into amino (Cel/G4-NH(2)) and hydroxyl (Cel/G4-OH) terminus poly(amidoamine) (G4) dendrimers. Cell viability, release of nitric oxide, IL-6, TNF-α and activation of MAPK (e.g., p38 and JNK) and NF-κB were assessed in endotoxin (i.e., lipopolysaccharide) stimulated microglial cells.
  
  
  RESULTS
  G4-OH and G4-NH(2) increased celastrol aqueous solubility by seven- and 12-fold, respectively. G4-OH and Cel/G4-OH suppressed lipopolysaccharide-mediated release of proinflammatory mediators, such as nitric oxide and IL-6, but not TNF-α, without reducing microglial cell viability, while Cel/G4-NH(2) potentiated cytotoxicity and cytokine release. Blockade of proinflammatory signaling was accompanied by attenuation of p38 MAPK activation.
  
  
  CONCLUSIONS
  This study supports the potential use of poly(amidoamine) dendrimers for effective anti-inflammatory therapy in the chronically inflamed CNS.
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Boridy
authors.forename: Ghareb M
authors.initials: GM
authors.lastname: Soliman
authors.forename: Dusica
authors.initials: D
authors.lastname: Maysinger
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology*; D050091:Dendrimers / Q000737:chemistry* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000276:immunology; D053978:Pentacyclic Triterpenes; D015398:Signal Transduction / Q000187:drug effects*; D029757:Tripterygium / Q000737:chemistry; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D050091:Dendrimers; D004337:Drug Carriers; D008070:Lipopolysaccharides; D016328:NF-kappa B; C104700:PAMAM Starburst; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; C050414:celastrol