title: Synthetic cryptolepine inhibits DNA binding of NF-kappaB.
abstract: The alkaloid cryptolepine is thought to mediate the anti-inflammatory effects of the climbing shrub, Cryptolepis sanguinoleta. The underlying mechanism of action, however, is largely unknown. In the present study, we show that the synthetic cryptolepine-hydrochloride (2.5-10microM) dose-dependently inhibits lipopolysaccharide (LPS)-induced nitric oxide production in the murine macrophage cell line RAW 264.7. We furthermore demonstrate a strong inhibition of nuclear factor (NF)-kappaB, a transcription factor primarily involved in inflammatory and immune responses, by cryptolepine (2.5-10microM) using a luciferase reporter gene assay in human HEK 293 cells. Examining the individual steps of NF-kappaB activation in the presence of cryptolepine we could exclude an inhibitory effect on degradation of IkappaB or nuclear translocation of NF-kappaB by the alkaloid. However, EMSA of nuclear extracts from LPS-activated RAW cells revealed reduced DNA binding activity of NF-kappaB by cryptolepine in vivo and in vitro. This indicates that cryptolepine may exhibit its anti-inflammatory action by blocking DNA binding of activated NF-kappaB and thus transcription of NF-kappaB-regulated proinflammatory proteins.
authors.affiliation: Department of Pharmacy, Center of Drug Research, University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany. maylajide@hotmail.com
authors.forename: Olumayokun A
authors.initials: OA
authors.lastname: Olajide
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
authors.forename: Daniel
authors.initials: D
authors.lastname: Schachner
authors.forename: Colin W
authors.initials: CW
authors.lastname: Wright
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D031106:Cryptolepis / Q000737:chemistry; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000470:Alkaloids; D000893:Anti-Inflammatory Agents; D026121:Indole Alkaloids; D007211:Indoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011804:Quinolines; D009569:Nitric Oxide; C024015:cryptolepine; D004247:DNA