title: The quassinoid isobrucein B reduces inflammatory hyperalgesia and cytokine production by post-transcriptional modulation.
abstract: Isobrucein B (1) is a quassinoid isolated from the Amazonian medicinal plant Picrolemma sprucei. Herein we investigate the anti-inflammatory and antihyperalgesic effects of this quassinoid. Isobrucein B (1) (0.5-5 mg/kg) inhibited carrageenan-induced inflammatory hyperalgesia in mice in a dose-dependent manner. Reduced hyperalgesia was associated with reduction in both neutrophil migration and pronociceptive cytokine production. Pretreatment with 1 inhibited in vitro production/release of cytokines TNF, IL-1β, and KC/CXCL1 by lipopolysaccharide-stimulated macrophages. To investigate its molecular mechanism, RAW 264.7 macrophages with a luciferase reporter gene controlled by the NF-κB promoter were used (RAW 264.7-Luc). Quassinoid 1 reduced the luminescence emission by RAW 264.7-Luc stimulated by different compounds. Unexpectedly, NF-κB translocation to macrophage nuclei was not inhibited by 1 when evaluated by Western blotting and immunofluorescence. Furthermore, quassinoid 1 did not change the levels of TNF mRNA transcription in stimulated macrophages, suggesting post-transcriptional modulation. In addition, constitutive expression of luciferase in RAW 264.7 cells transiently transfected with a plasmid containing a universal promoter was inhibited by 1. Thus, isobrucein B (1) displays anti-inflammatory and antihyperalgesic activities by nonselective post-transcriptional modulation, resulting in decreased production/release of pro-inflammatory cytokines and neutrophil migration.
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo , São Paulo, Brazil.
authors: Rangel L
authors: RL
authors: Silva
authors: Alexandre H
authors: AH
authors: Lopes
authors: Rafael O
authors: RO
authors: França
authors: Sílvio M
authors: SM
authors: Vieira
authors: Ellen C C
authors: EC
authors: Silva
authors: Rodrigo C N
authors: RC
authors: Amorim
authors: Fernando Q
authors: FQ
authors: Cunha
authors: Adrian M
authors: AM
authors: Pohlit
authors: Thiago M
authors: TM
authors: Cunha
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001938:Brazil; D002351:Carrageenan / Q000009:adverse effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy*; D020672:I-kappa B Proteins / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry*; D036702:Quassins / Q000737:chemistry / Q000494:pharmacology*; D029641:Simaroubaceae / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D036702:Quassins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C076339:isobrucein B; D002351:Carrageenan; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone