title: Anti-inflammatory and analgesic activity of carnosol and carnosic acid in vivo and in vitro and in silico analysis of their target interactions.
abstract: The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets.
  
  
  
  The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E2synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) was confirmed by CS and CA, and we determined the consequence on the eicosanoid network in activated human primary monocytes and neutrophils. Molecular interactions and binding modes of CS and CA to target enzymes were analyzed by docking studies.
  
  
  
  CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan-induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors.
  
  
  
  In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti-inflammatory remedy, in the continuous expanding context of nutraceuticals.
  
  
  
  This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Maione
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Cantone
authors.affiliation: Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.affiliation: Department of Pharmacy, University of Genoa, Genoa, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bisio
authors.affiliation: Department of Pharmacy, University of Genoa, Genoa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romussi
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pieretti
authors.affiliation: Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Mascolo
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D045784:Abietanes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D000700:Analgesics / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D003198:Computer Simulation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors; D027544:Salvia / Q000737:chemistry
chemical_list: D045784:Abietanes; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; C068623:carnosol; D000071876:Prostaglandin-E Synthases; C018381:salvin