title: Gastro-protective effects of isobrucein B, a quassinoid isolated from Picrolemma sprucei.
abstract: Infusions of Picrolemma sprucei roots, stems and leaves are used in traditional medicine throughout the Amazon region from the Guianas to Brazil and Peru in the treatment of gastritis, intestinal helminths and malaria. As there are no studies describing its mode of action in providing a gastroprotective effect, we determined herein that one of the main constituents found in P. sprucei infusions, the quassinoid isobrucein B (IsoB), reduces some of the pathophysiological effects in a mouse model of non-steroidal anti-inflammatory drug (NSAID)-induced gastritis and provides mechanisms of action. Then, IsoB (1.17 g) was isolated from the roots and stems (6.5 kg) of P. sprucei. Its structure was confirmed by 1D and 2D (1)H and (13)C NMR, ESI-tof-MS, IR and UV. C57BL/6 strain mice were subcutaneously injected with IsoB (0.5-5 mg kg(-1)) or vehicle before oral administration of indomethacin and sacrificed later at different time points. Gastric damage was assessed by measuring lesion length. Leukocyte migration was evaluated based on leukocyte rolling and adhesion using intravital microscopy in the mesenteric microcirculation and tissue MPO activity. Stomach extract cytokine (TNFα, IL-1β and KC/CXCL1) and prostaglandin E2 (PGE2) levels were measured by ELISA and RIA, respectively. IsoB pre-treatment (0.5-5.0 mg kg(-1)) significantly reduced the formation of indomethacin-induced stomach lesions in a dose-dependent manner. The decrease in stomach lesions was associated with less observed leukocyte rolling, decreased leukocyte adhesion and less neutrophil infiltration (MPO activity). IsoB (1 mg kg(-1)) pre-treatment did not prevent indomethacin-induced decreases in stomach PGE2 levels. However, IL-1β and KC/CXCL1 levels were inhibited by this same IsoB dosage, whereas TNF-α was unchanged. IsoB may be a prototypic compound to provide protective effects against NSAID-induced gastritis and possibly other gastropathies. Moreover, IsoB gastroprotective action may be due to a reduction in IL-1β and KC/CXCL1 production/release and leukocyte rolling, adhesion and migration.
authors.affiliation: National Institute for Research in the Amazon (INPA), Av Andre Araújo 2936, CEP 69060-001, Manaus, Amazonas State, Brazil; Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo State, Brazil.
authors.forename: Sílvio Manfredo
authors.initials: SM
authors.lastname: Vieira
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo State, Brazil.
authors.forename: Rangel Leal
authors.initials: RL
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo State, Brazil.
authors.forename: Henrique Paula
authors.initials: HP
authors.lastname: Lemos
authors.affiliation: National Institute for Research in the Amazon (INPA), Av Andre Araújo 2936, CEP 69060-001, Manaus, Amazonas State, Brazil.
authors.forename: Rodrigo César das Neves
authors.initials: RC
authors.lastname: Amorim
authors.affiliation: National Institute for Research in the Amazon (INPA), Av Andre Araújo 2936, CEP 69060-001, Manaus, Amazonas State, Brazil.
authors.forename: Ellen Cristina Costa
authors.initials: EC
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo State, Brazil.
authors.forename: Peter Sol
authors.initials: PS
authors.lastname: Reinach
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo State, Brazil.
authors.forename: Fernando Queiróz
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: National Institute for Research in the Amazon (INPA), Av Andre Araújo 2936, CEP 69060-001, Manaus, Amazonas State, Brazil. Electronic address: ampohlit@inpa.gov.br.
authors.forename: Adrian Martin
authors.initials: AM
authors.lastname: Pohlit
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo State, Brazil. Electronic address: thicunha@usp.br.
authors.forename: Thiago Mattar
authors.initials: TM
authors.lastname: Cunha
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy*; D007213:Indomethacin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D018517:Plant Roots / Q000737:chemistry; D018547:Plant Stems / Q000737:chemistry; D010946:Plants, Medicinal; D036702:Quassins / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D029641:Simaroubaceae / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D010936:Plant Extracts; D036702:Quassins; C076339:isobrucein B; D015232:Dinoprostone; D007213:Indomethacin
keywords: Cytokines; Gastropathy; Indomethacin (PubChem CID 23675763); Isobrucein B; Isobrucein B (PubChem CID 99530); Leukocytes; Quassinoid