title: The hallucinogenic diterpene salvinorin A inhibits leukotriene synthesis in experimental models of inflammation.
abstract: Leukotrienes (LTs) are lipid mediators derived from arachidonic acid (AA) involved in a number of autoimmune/inflammatory disorders including asthma, allergic rhinitis and cardiovascular diseases. Salvinorin A (SA), a diterpene isolated from the hallucinogenic plant Salvia divinorum, is a well-established analgesic compound, but its anti-inflammatory properties are under-researched and its effects on LT production is unknown to date. Here, we studied the possible effect of SA on LT production and verified its actions on experimental models of inflammation in which LTs play a prominent role. Peritoneal macrophages (PM) stimulated by calcium ionophore A23187 were chosen as in vitro system to evaluate the effect of SA on LT production. Zymosan-induced peritonitis in mice and carrageenan-induced pleurisy in rats were selected as LT-related models to evaluate the effect of SA on inflammation as well as on LT biosynthesis. SA inhibited, in a concentration-dependent manner, A23187-induced LTB4 biosynthesis in isolated PM. In zymosan-induced peritonitis, SA inhibited cell infiltration, myeloperoxidase activity, vascular permeability and LTC4 production in the peritoneal cavity without decreasing the production of prostaglandin E2. In carrageenan-induced pleurisy in rats, a more sophisticated model of acute inflammation related to LTs, SA significantly inhibited LTB4 production in the inflammatory exudates, along with reducing the phlogistic process in the lung. In conclusion, SA inhibited LT production and it was effective in experimental models of inflammation in which LTs play a pivotal role. SA might be considered as a lead compound for the development of drugs useful in LTs-related diseases.
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy. Electronic address: antrossi@unina.it.
authors: Antonietta
authors: A
authors: Rossi
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy; Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, Jena, Germany. Electronic address: simona.pace@uni-jena.de.
authors: Simona
authors: S
authors: Pace
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy. Electronic address: fed.tedesco@gmail.com.
authors: Federica
authors: F
authors: Tedesco
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy. Electronic address: ester.pagano@unina.it.
authors: Ester
authors: E
authors: Pagano
authors: Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: germano.guerra@unimol.it.
authors: Germano
authors: G
authors: Guerra
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, Jena, Germany. Electronic address: fabiana.troisi@uni-jena.de.
authors: Fabiana
authors: F
authors: Troisi
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, Jena, Germany. Electronic address: werner.markus@uni-jena.de.
authors: Markus
authors: M
authors: Werner
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy. Electronic address: fiorentina.roviezzo@unina.it.
authors: Fiorentina
authors: F
authors: Roviezzo
authors: Department of BioMolecular Sciences, Division of Pharmacognosy and the Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. Electronic address: jordan@olemiss.edu.
authors: Jordan K
authors: JK
authors: Zjawiony
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
authors: Oliver
authors: O
authors: Werz
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy. Electronic address: aaizzo@unina.it.
authors: Angelo A
authors: AA
authors: Izzo
authors: Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy. Electronic address: rafcapas@unina.it.
authors: Raffaele
authors: R
authors: Capasso
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D006213:Hallucinogens / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D051381:Rats; D017208:Rats, Wistar; D015054:Zymosan / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D006213:Hallucinogens; D020024:Leukotriene Antagonists; D007975:Leukotriene B4; D016718:Arachidonic Acid; D015054:Zymosan; C090499:salvinorin A
keywords: Ca(2+)-ionophore A23187 (PubChem CID: 11957499); Inflammation; Leukotriene B(4) (PubMed CID: 5280492); Leukotriene C(4) (PubMed CID: 5283121); Leukotrienes; Peritonitis; Pleurisy; Prostaglandin E(2) (PubChem CID: 5280360); Salvinorin A; Zymosan (PubMed CID:11375554)