title: Caffeic acid phenethyl ester (CAPE): scavenger of peroxynitrite in vitro and in sepsis models.
abstract: Excessive free radical production by immune cells has been linked to cell death and tissue injury during sepsis. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death that has been identified in several pathological conditions. Caffeic acid phenethyl ester (CAPE) is an active component of honeybee products and exhibits antioxidant, anti-inflammatory, and immunomodulatory activities. The present study examined the ability of CAPE to scavenge peroxynitrite in RAW 264.7 murine macrophages stimulated with lipopolysaccharide/interferon-γ that was used as an in vitro model. Conversion of 123-dihydrorhodamine to its oxidation product 123-rhodamine was used to measure peroxynitrite production. Two mouse models of sepsis (endotoxemia and cecal ligation and puncture) were used as in vivo models. The level of serum 3-nitrotyrosine was used as an in vivo marker of peroxynitrite. The results demonstrated that CAPE significantly improved the viability of lipopolysaccharide/interferon-γ-treated RAW 264.7 cells and significantly inhibited nitric oxide production, with effects similar to those observed with an inhibitor of inducible nitric oxide synthase (1400W). In addition, CAPE exclusively inhibited the synthesis of peroxynitrite from the artificial substrate SIN-1 and directly prevented the peroxynitrite-mediated conversion of dihydrorhodamine-123 to its fluorescent oxidation product rhodamine-123. In both sepsis models, CAPE inhibited cellular peroxynitrite synthesis, as evidenced by the absence of serum 3-nitrotyrosine, an in vivo marker of peroxynitrite. Thus, CAPE attenuates the inflammatory responses that lead to cell damage and, potentially, cell death through suppression of the production of cytotoxic molecules such as nitric oxide and peroxynitrite. These observations provide evidence of the therapeutic potential of CAPE treatment for a wide range of inflammatory disorders.
authors.affiliation: *Departments of Anesthesiology, †Ophthalmology, ‡Medical Microbiology, §Rehabilitation Medicine, and ∥Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; and ¶Department of Molecular Biology and Genetics, Faculty of Arts and Science, Canik Basari University, Samsun, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Kassim
authors.forename: Marzida
authors.initials: M
authors.lastname: Mansor
authors.forename: Tengku Ain
authors.initials: TA
authors.lastname: Kamalden
authors.forename: Ina Ismiarti
authors.initials: II
authors.lastname: Shariffuddin
authors.forename: Mohd Shahnaz
authors.initials: MS
authors.lastname: Hasan
authors.forename: Gracie
authors.initials: G
authors.lastname: Ong
authors.forename: Shamala Devi
authors.initials: SD
authors.lastname: Sekaran
authors.forename: Anwar
authors.initials: A
authors.lastname: Suhaimi
authors.forename: Nazeh
authors.initials: N
authors.lastname: Al-Abd
authors.forename: Kamaruddin Mohd
authors.initials: KM
authors.lastname: Yusoff
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D002109:Caffeic Acids; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D007371:Interferon-gamma; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol