title: Perthamide C inhibits eNOS and iNOS expression and has immunomodulating activity in vivo.
abstract: Here we have characterized perthamide C, a cyclopeptide from a Solomon Lithistid sponge Theonella swinhoei, which displays an anti-inflammatory/immunomodulatory activity. The study has been performed using the carragenan-induced mouse paw edema that displays an early (0-6 h) and a late phase (24-96 h). Perthamide C significantly inhibits neutrophils infiltration in tissue both in the early and late phases. This effect was coupled to a reduced expression of the endothelial nitric oxide synthase (eNOS) in the early phase while cyclooxygenase-1 and 2 (COX-1, COX-2), and inducible NOS (iNOS) expression were unaffected. In the late phase perthamide C reduced expression of both NOS isoforms without affecting COXs expression. This peculiar selectivity toward the two enzymes deputed to produce NO lead us to investigate on a possible action of perthamide C on lymphocytes infiltration and activation. We found that perthamide C inhibited the proliferation of peripheral lymphocytes, and that this effect was secondary to its metabolic activation in vivo. Indeed, in vitro perthamide C did not inhibit proliferation as opposite to its metabolite perthamide H. In conclusion, perthamide C selectively interferes with NO generation triggered by either eNOS or iNOS without affecting either COX-1 or COX-2. This in turn leads to modulation of the inflammatory response through a reduction of vascular permeability, neutrophil infiltration as well as lymphocyte proliferation.
authors.affiliation: Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.forename: Anna
authors.initials: A
authors.lastname: Cantalupo
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Panza
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.forename: Angela
authors.initials: A
authors.lastname: Ianaro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000276:immunology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000276:immunology; D010456:Peptides, Cyclic / Q000494:pharmacology*
chemical_list: D007155:Immunologic Factors; D008565:Membrane Proteins; D010456:Peptides, Cyclic; C574057:perthamide C; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse
references.citation: Immunology. 1994 Jul;82(3):370-5
references.pmid: 7959870
references.citation: Org Lett. 2011 Mar 18;13(6):1532-5
references.pmid: 21341715
references.citation: Nature. 1998 Apr 23;392(6678):821-4
references.pmid: 9580552
references.citation: J Med Chem. 2011 Jul 14;54(13):4590-9
references.pmid: 21599020
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):904-8
references.pmid: 15640348
references.citation: Immunology. 1995 Jan;84(1):8-15
references.pmid: 7890306
references.citation: J Med Chem. 2011 Jan 13;54(1):401-5
references.pmid: 21141967
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1998 Oct;358(4):489-95
references.pmid: 9826072
references.citation: Mol Biosyst. 2012 Apr;8(5):1412-7
references.pmid: 22327116
references.citation: Br J Pharmacol. 2004 May;142(2):331-8
references.pmid: 15155540
references.citation: Dermatol Online J. 1999 May;5(1):7
references.pmid: 10673450
references.citation: Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii37-40
references.pmid: 17038470
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Nov 5;826(1-2):147-59
references.pmid: 16182619
references.citation: Curr Opin Investig Drugs. 2006 Nov;7(11):974-9
references.pmid: 17117584