Immunomodulatory Lipids in Plants: Plant Fatty Acid Amides and the Human Endocannabinoid System

Abstract

Since the discovery that endogenous lipid mediators show similar cannabimimetic effects as phytocannabinoids from Cannabis sativa, our knowledge about the endocannabinoid system has rapidly expanded. Today, endocannabinoid action is known to be involved in various diseases, including inflammation and pain. As a consequence, the G-protein coupled cannabinoid receptors, endocannabinoid transport, as well as endocannabinoid metabolizing enzymes represent targets to block or enhance cannabinoid receptor-mediated signalling for therapeutic intervention. Based on the finding that certain endocannabinoid-like fatty acid N-alkylamides from purple coneflower (Echinacea spp.) potently activate CB₂ cannabinoid receptors we have focused our interest on plant fatty acid amides (FAAs) and their overall cannabinomodulatory effects. Certain FAAs are also able to partially inhibit the action of fatty acid amide hydrolase (FAAH), which controls the breakdown of endocannabinoids. Intriguingly, plants lack CB receptors and do not synthesize endocannabinoids, but express FAAH homologues capable of metabolizing plant endogenous N-acylethanolamines (NAEs). While the site of action of these NAEs in plants is unknown, endogenous NAEs and arachidonic acid glycerols in animals interact with distinct physiological lipid receptors, including cannabinoid receptors. There is increasing evidence that also plant FAAs other than NAEs can pharmacologically modulate the action of these endogenous lipid signals. The interference of plant FAAs with the animal endocannabinoid system could thus be a fortunate evolutionary cross point with yet unexplored therapeutic potential.

Key words

Echinacea - endocannabinoid system - fatty acid N-alkylamides - immunomodulatory lipids - N-acylethanolamines - lipidomics - cannabinoid

References

• 1 Fahy E, Subramaniam S, Brown H A, Glass C K, Merrill AH J r, Murphy R C. et al . A comprehensive classification system for lipids.  J Lipid Res. 2005;  46 839-61
• 2 Aguilar P S, de Mendoza D. Control of fatty acid desaturation: a mechanism conserved from bacteria to humans.  Mol Microbiol. 2006;  62 1507-14
• 3 Wenk M R. Lipidomics of host-pathogen interactions.  FEBS Lett. 2006;  580 5541-51
• 4 Holman RT,George O. Burr and the discovery of essential fatty acids.  J Nutr. 1988;  118 535-40
• 5 Vane J R. Antiinflammatory drugs and the many mediators of inflammation.  Int J Tissue React. 1987;  9 1-14
• 6 Vane J R, Botting R M. The mode of action of anti-inflammatory drugs.  Postgrad Med J. 1990;  66 (Suppl.) S2-17
• 7 Higgs G A, Moncada S, Vane J R. Eicosanoids in inflammation.  Ann Clin Res. 1984;  16 287-99
• 8 Baker R R. The eicosanoids: a historical overview.  Clin Biochem. 1990;  23 455-8
• 9 Benveniste J. Paf-acether, an ether phospho-lipid with biological activity.  Prog Clin Biol Res. 1988;  282 73-85
• 10 Demopoulos C A, Antonopoulou S. A discovery trip to compounds with PAF-like activity.  Adv Exp Med Biol. 1996;  416 59-63
• 11 Sakane F, Imai S, Kai M, Yasuda S, Kanoh H. Diacylglycerol kinases: why so many of them?.  Biochim Biophys Acta. 2007;  1771 793-806
• 12 Shemarova I V. Phosphoinositide signaling in unicellular eukaryotes.  Crit Rev Microbiol. 2007;  33 141-56
• 13 Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T. Identification of GPR55 as a lysophosphatidylinositol receptor.  Biochem Biophys Res Commun. 2007;  362 28-34
• 14 Pertwee R G. GPR55: a new member of the cannabinoid receptor clan?. Br J Pharmacol 2007, in press
• 15 Ghosh S, Strum J C, Bell R M. Lipid biochemistry: functions of glycerolipids and sphingolipids in cellular signaling.  FASEB J. 1997;  11 45-50
• 16 Serhan C N. Novel chemical mediators in the resolution of inflammation: resolvins and protectins.  Anesthesiol Clin. 2006;  24 341-64
• 17 Wenk M R. The emerging field of lipidomics.  Nat Rev Drug Discov. 2005;  4 594-610
• 18 Fritsche K. Fatty acids as modulators of the immune response.  Annu Rev Nutr. 2006;  26 45-73
• 19 de Pablo M A, Puertollano M A, Alvarez de Cienfuegos G. Biological and clinical significance of lipids as modulators of immune system functions.  Clin Diagn Lab Immunol. 2002;  9 945-50
• 20 Brown A J. Novel cannabinoid receptors. Br J Pharmacol 2007, in press
• 21 Starowicz K, Nigam S, Di Marzo V. Biochemistry and pharmacology of endovanilloids.  Pharmacol Ther. 2007;  114 13-33
• 22 Duval C, Muller M, Kersten S. PPARalpha and dyslipidemia.  Biochim Biophys Acta. 2007;  1771 961-71
• 23 Torkhovskaya T I, Ipatova O M, Zakharova T S, Kochetova M M, Khalilov E M. Lysophospholipid receptors in cell signaling.  Biochemistry (Moscow). 2007;  72 125-31
• 24 Romano M, Recchia I, Recchiuti A. Lipoxin receptors.  ScientificWorldJournal. 2007;  7 1393-412
• 25 German J B, Gillies L A, Smilowitz J T, Zivkovic A M, Watkins S M. Lipidomics and lipid profiling in metabolomics.  Curr Opin Lipidol. 2007;  18 66-71
• 26 Elphick M R, Egertova M. The phylogenetic distribution and evolutionary origins of endocannabinoid signalling.  Handb Exp Pharmacol. 2005;  168 283-97
• 27 Di Marzo V, Petrocellis L D. Plant, synthetic, and endogenous cannabinoids in medicine.  Annu Rev Med. 2006;  57 553-74
• 28 Kogan N M, Mechoulam R. The chemistry of endocannabinoids.  J Endocrinol Invest. 2006;  29 3-14
• 29 Pertwee R G. The diverse CB(1) and CB(2) receptor pharmacology of three plant cannabinoids: Delta(9)-tetrahydrocannabinol, cannabidiol and delta(9)-tetrahydrocannabivarin. Br J Pharmacol 2007, in press
• 30 Pavlopoulos S, Thakur G A, Nikas S P, Makriyannis A. Cannabinoid receptors as therapeutic targets.  Curr Pharm Des. 2006;  12 1751-69
• 31 Mechonlam R, Gaoni Y. Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids.  Tetrahedron. 1965;  21 1223-9
• 32 Mechoulam R. Marihuana chemistry.  Science. 1970;  168 1159-66
• 33 Devane W A, Dysarz FA 3 rd, Johnson M R, Melvin L S, Howlett A C. Determination and characterization of a cannabinoid receptor in rat brain.  Mol Pharmacol. 1988;  34 605-13
• 34 Herkenham M, Lynn A B, de Costa B R, Richfield E K. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat.  Brain Res. 1991;  547 267-74
• 35 Matsuda L A, Lolait S J, Brownstein M J, Young A C, Bonner T I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.  Nature. 1990;  346 561-4
• 36 Munro S, Thomas K L, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids.  Nature. 1993;  365 61-5
• 37 Howlett A C. Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes.  Mol Pharmacol. 1985;  27 429-36
• 38 Devane W A, Dysarz FA 3 rd, Johnson M R, Melvin L S, Howlett A C. Determination and characterization of a cannabinoid receptor in rat brain.  Mol Pharmacol. 1988;  34 605-13
• 39 Ward S J, Baizman E, Bell M, Childers S, D′Ambra T, Eissenstat M. et al . Aminoalkylindoles (AAIs): a new route to the cannabinoid receptor?.  NIDA Res Monogr. 1990;  105 425-6
• 40 Herkenham M, Lynn A B, Little M D, Johnson M R, Melvin L S. et al . Cannabinoid receptor localization in brain.  Proc Natl Acad Sci USA. 1990;  87 1932-6
• 41 Mailleux P, Vanderhaeghen J J. Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons.  Neurosci Lett. 1992;  148 173-6
• 42 Cabral G A, Marciano-Cabral F. Cannabinoid receptors in microglia of the central nervous system: immune functional relevance.  J Leukoc Biol. 2005;  78 1192-7
• 43 Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system.  Handb Exp Pharmacol. 2005;  168 299-325
• 44 Gong J P, Onaivi E S, Ishiguro H, Liu Q R, Tagliaferro P A, Brusco A. et al . Cannabinoid CB2 receptors: immunohistochemical localization in rat brain.  Brain Res. 2006;  1071 10-23
• 45 Onaivi E S, Ishiguro H, Gong J P, Patel S, Perchuk A, Meozzi P A. et al . Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain.  Ann NY Acad Sci. 2006;  1074 514-36
• 46 Howlett A C, Barth F, Bonner T I, Cabral G, Casellas P, Devane W A. et al . International Union of Pharmacology, XXVII. Classification of cannabinoid receptors.  Pharmacol Rev. 2002;  54 161-202
• 47 Howlett A C. Cannabinoid receptor signalling.  Handb Exp Pharmacol. 2005;  168 53-79
• 48 Demuth D G, Molleman A. Cannabinoid signalling.  Life Sci. 2006;  78 549-63
• 49 Devane W A, Hanus L, Breuer A, Pertwee R G, Stevenson L A, Griffin G. et al . Isolation and structure of a brain constituent that binds to the cannabinoid receptor.  Science. 1992;  258 1946-9
• 50 Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz J C. et al . Formation and inactivation of endogenous cannabinoid anandamide in central neurons.  Nature. 1994;  372 686-91
• 51 Thomas B F, Adams I B, Mascarella S W, Martin B R, Razdan R K. Structure-activity analysis of anandamide analogs: relationship to a cannabinoid pharmacophore.  J Med Chem. 1996;  39 471-9
• 52 Okamoto Y, Wang J, Morishita J, Ueda N. Biosynthetic pathways of the endocannabinoid anandamide.  Chem Biodivers. 2007;  4 1842-57
• 53 Ligresti A, Cascio M G, Di Marzo V. Endocannabinoid metabolic pathways and enzymes.  Curr Drug Targets CNS Neurol Disord. 2005;  4 615-23
• 54 Mechoulam R, Fride E, Di Marzo V. Endocannabinoids.  Eur J Pharmacol. 1998;  359 1-18
• 55 Klein T W, Newton C, Larsen K, Lu L, Perkins I, Nong L. et al . The cannabinoid system and immune modulation.  J Leukoc Biol. 2003;  74 486-96
• 56 Pertwee R G. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids.  AAPS J. 2005;  7 E625-54
• 57 Hanus L O. Discovery and isolation of anandamide and other endocannabinoids.  Chem Biodivers. 2007;  4 1828-41
• 58 Kogan N M, Mechoulam R. The chemistry of endocannabinoids.  J Endocrinol Invest. 2006;  29 3-14
• 59 Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz J C. et al . Formation and inactivation of endogenous cannabinoid anandamide in central neurons.  Nature. 1994;  372 686-91
• 60 Cadas H, Gaillet S, Beltramo M, Venance L, Piomelli D. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP.  J Neurosci. 1996;  16 3934-42
• 61 Beltramo M, Stella N, Calignano A, Lin S Y, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition.  Science. 1997;  277 1094-7
• 62 Cravatt B F, Giang D K, Mayfield S P, Boger D L, Lerner R A, Gilula N B. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.  Nature. 1996;  384 83-7
• 63 Caterina M J, Schumacher M A, Tominaga M, Rosen T A, Levine J D, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway.  Nature. 1997;  389 816-24
• 64 Akerman S, Kaube H, Goadsby P J. Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors.  Br J Pharmacol. 2004;  142 1354-60
• 65 Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson N O, Leonova J. et al . The orphan receptor GPR55 is a novel cannabinoid receptor.  Br J Pharmacol. 2007;  152 1092-110
• 66 Brown A J. Novel cannabinoid receptors.  Br J Pharmacol. 2007;  152 567-75
• 67 Appendino G, Minassi A, Berton L, Moriello A S, Cascio M G, De Petrocellis L. et al . Oxyhomologues of anandamide and related endolipids: chemoselective synthesis and biological activity.  J Med Chem. 2006;  49 2333-8
• 68 Appendino G, Cascio M G, Bacchiega S, Moriello A S, Minassi A, Thomas A. et al . First ”hybrid” ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands.  FEBS Lett. 2006;  580 568-74
• 69 Mahadevan A, Razdan R K. Further advances in the synthesis of endocannabinoid-related ligands.  AAPS J. 2005;  7 E496-502
• 70 Kogan N M, Mechoulam R. The chemistry of endocannabinoids.  J Endocrinol Invest. 2006;  29 3-14
• 71 Raduner S, Majewska A, Chen J Z, Xie X Q, Hamon J, Faller B. et al . Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects.  J Biol Chem. 2006;  281 14 192-206
• 72 Gertsch J, Raduner S, Altmann K H. New natural noncannabinoid ligands for cannabinoid type-2 (CB2) receptors.  J Recept Signal Transduct Res. 2006;  26 709-30
• 73 Raduner S, Chicca A, Feyen F, Khan I, Altmann K -H, Gertsch J. Exploration of natural and synthetic N-alkyl amides as source for new lead structures to target the endocannabinoid system. ICRS meeting 2007, Saint Sauveur, Canada;
• 74 Lopez-Bucio J, Acevedo-Hernandez G, Ramirez-Chavez E, Molina-Torres J, Herrera-Estrella L. Novel signals for plant development.  Curr Opin Plant Biol. 2006;  9 523-9
• 75 Chapman K D. Occurrence, metabolism, and prospective functions of N-acylethanolamines in plants.  Prog Lipid Res. 2004;  43 302-27
• 76 Doskotch R W, Beal J L. The isolation and identification of the numbing principle in Chrysanthemum anethifolium.  Lloydia. 1970;  33 393-4
• 77 Achenbach H, Fietz W, Worth J, Waibel R, Portecop J. Constituents of tropical medicinal plants, IXX1 GC/MS-investigations of the constituents of Piper amalago - 30 new amides of the piperine-type.  Planta Med. 1986;  52 12-8
• 78 Muller-Jakic B, Breu W, Probstle A, Redl K, Greger H, Bauer R. In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from Echinacea and Achillea species.  Planta Med. 1994;  60 37-40
• 79 Ramsewak R S, Erickson A J, Nair M G. Bioactive N-isobutylamides from the flower buds of Spilanthes acmella.  Phytochemistry. 1999;  51 729-32
• 80 Bohlmann F, Zdero C, Suwita A. Weitere Amide aus der Tribus Anthemideae.  Chem Ber.. 1974;  107 1038-43
• 81 Nakatani N, Inatani R, Ohta H, Nishioka A. Chemical constituents of peppers (Piper spp.) and application to food preservation: naturally occurring antioxidative compounds.  Environ Health Perspect. 1986;  67 135-42
• 82 Muhammad I, Zhao J, Dunbar D C, Khan I A. Constituents of Lepidium meyenii ‘maca’.  Phytochemistry. 2002;  59 105-10
• 83 Zhao J, Muhammad I, Dunbar D C, Mustafa J, Khan I A. New alkamides from maca (Lepidium meyenii).  J Agric Food Chem. 2005;  53 690-3
• 84 Pei Y Q. A review of pharmacology and clinical use of piperine and its derivatives.  Epilepsia. 1983;  24 177-82
• 85 Greger H. Alkamides: structural relationships, distribution and biological activity.  Planta Med. 1984;  50 366-75
• 86 Bauer R, Remiger P, Wagner H. New alkamides from Echinacea angustifolia and E. purpurea roots.  Planta Med. 1988;  54 563-4
• 87 Dembitsky V M, Shkrob I, Rozentsvet O A. Fatty acid amides from freshwater green alga Rhizoclonium hieroglyphicum.  Phytochemistry. 2000;  54 965-7
• 88 Sitachitta N, Gerwick W H. Grenadadiene and grenadamide, cyclopropyl-containing fatty acid metabolites from the marine cyanobacterium Lyngbya majuscula.  J Nat Prod. 1998;  61 681-4
• 89 Avery T D, Culbert J A, Taylor D K. The first total synthesis of natural grenadamide.  Org Biomol Chem. 2006;  4 323-30
• 90 Chapman K D. Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection.  Chem Phys Lipids. 2000;  108 221-9
• 91 Chapman K D, Tripathy S, Venables B, Desouza A D. N-Acylethanolamines: formation and molecular composition of a new class of plant lipids.  Plant Physiol. 1998;  116 1163-8
• 92 Chapman K D. Occurrence, metabolism, and prospective functions of N-acylethanolamines in plants.  Prog Lipid Res. 2004;  43 302-27
• 93 Ramirez-Chavez E, Lopez-Bucio J, Herrera-Estrella L, Molina-Torres J. Alkamides isolated from plants promote growth and alter root development in Arabidopsis.  Plant Physiol. 2004;  134 1058-68
• 94 Lopez-Bucio J, Millan-Godinez M, Mendez-Bravo A, Morquecho-Contreras A, Ramirez-Chavez E, Molina-Torres J. et al .Cytokinin receptors are involved in alkamide regulation of root and shoot development in Arabidopsis thaliana. Plant Physiol 2007, in press
• 95 Wang Y S, Shrestha R, Kilaru A, Wiant W, Venables B J, Chapman K D. et al . Manipulation of Arabidopsis fatty acid amide hydrolase expression modifies plant growth and sensitivity to N-acylethanolamines.  Proc Natl Acad Sci USA. 2006;  103 12 197-202
• 96 Jonsson K O, Vandevoorde S, Lambert D M, Tiger G, Fowler C J. Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide.  Br J Pharmacol. 2001;  133 1263-75
• 97 McKinney M K, Cravatt B F. Structure-based design of a FAAH variant that discriminates between the N-acyl ethanolamine and taurine families of signaling lipids.  Biochemistry. 2006;  45 9016-22
• 98 Woelkart K, Xu W, Pei Y, Makriyannis A, Picone R P, Bauer R. The endocannabinoid system as a target for alkamides from Echinacea angustifolia roots.  Planta Med. 2005;  71 701-5
• 99 Siddiqui B S, Gulzar T, Begum S, Afshan F, Sattar F A. Insecticidal amides from fruits of Piper nigrum Linn.  Nat Prod Res. 2005;  19 143-50
• 100 Zlotkin E. The insect voltage-gated sodium channel as target of insecticides.  Annu Rev Entomol. 1999;  44 429-55
• 101 Tsao R, Marvin C H, Broadbent A B, Friesen M, Allen W R, McGarvey B D. Evidence for an isobutylamide associated with host-plant resistance to western flower thrips, Frankliniella occidentalis, in chrysanthemum.  J Chem Ecol. 2005;  31 103-10
• 102 Wakamatsu K, Masaki T, Itoh F, Kondo K, Sudo K. Isolation of fatty acid amide as an angiogenic principle from bovine mesentery.  Biochem Biophys Res Commun. 1990;  168 423-9
• 103 Jaffe K, Blum M S, Fales H, Mason R, Cabrera A. On insect attractants from pitcher plants of the genus Heliamphora (Sarraceniaceae).  J Chem Ecol. 1995;  21 379-84
• 104 Cravatt B F, Prospero-Garcia O, Siuzdak G, Gilula N B, Henriksen S J, Boger D L. et al . Chemical characterization of a family of brain lipids that induce sleep.  Science. 1995;  268 1506-9
• 105 Huitron-Resendiz S, Gombart L, Cravatt B F, Henriksen S J. Effect of oleamide on sleep and its relationship to blood pressure, body temperature, and locomotor activity in rats.  Exp Neurol. 2001;  172 235-43
• 106 Kilaru A, Blancaflor E B, Venables B J, Tripathy S, Mysore K S, Chapman K D. The N-acylethanolamine-mediated regulatory pathway in plants.  Chem Biodivers. 2007;  4 1933-55
• 107 Bruzzone S, Moreschi I, Usai C, Guida L, Damonte G, Salis A. et al . Abscisic acid is an endogenous cytokine in human granulocytes with cyclic ADP-ribose as second messenger.  Proc Natl Acad Sci U S A. 2007;  104 5759-64
• 108 di Tomaso E, Beltramo M, Piomelli D. Brain cannabinoids in chocolate.  Nature. 1996;  382 677-8
• 109 Tytgat J, Van Boven M, Daenens P. Cannabinoid mimics in chocolate utilized as an argument in court.  Int J Legal Med. 2000;  113 137-9
• 110 Ueda N, Yamanaka K, Yamamoto S. Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance.  J Biol Chem.. 2001;  276 35 552-7
• 111 Movahed P, Jonsson B A, Birnir B, Wingstrand J A, Jorgensen T D, Ermund A. et al . Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists.  J Biol Chem. 2005;  280 38 496-504
• 112 Matthias A, Addison R S, Penman K G, Dickinson R G, Bone K M, Lehmann R P. Echinacea alkamide disposition and pharmacokinetics in humans after tablet ingestion.  Life Sci. 2005;  77 2018-29
• 113 Woelkart K, Koidl C, Grisold A, Gangemi J D, Turner R B, Marth E. et al . Bioavailability and pharmacokinetics of alkamides from the roots of Echinacea angustifolia in humans.  J Clin Pharmacol. 2005;  45 683-9
• 114 Raduner S, Bisson W, Abagyan R, Altmann K H, Gertsch J. Self-assembling cannabinomimetics: supramolecular structures of N-alkyl amides.  J Nat Prod. 2007;  70 1010-5
• 115 Barnes J, Anderson L A, Gibbons S, Phillipson J D. Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties.  J Pharm Pharmacol. 2005;  57 929-54
• 116 Woelkart K, Bauer R. The role of alkamides as an active principle of Echinacea.  Planta Med. 2007;  73 615-23
• 117 De Petrocellis L, Di Marzo V. Lipids as regulators of the activity of transient receptor potential type V1 (TRPV1) channels.  Life Sci. 2005;  77 1651-66
• 118 Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T. et al . Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells.  J Biol Chem. 2000;  275 605-12
• 119 Zoratti C, Kipmen-Korgun D, Osibow K, Malli R, Graier W F. Anandamide initiates Ca(2+) signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells.  Br J Pharmacol. 2003;  140 1351-62
• 120 Hinz B, Woelkart K, Bauer R. Alkamides from Echinacea inhibit cyclooxygenase-2 activity in human neuroglioma cells.  Biochem Biophys Res Commun. 2007;  360 441-6
• 121 LaLone C A, Hammer K D, Wu L, Bae J, Leyva N, Liu Y. et al . Echinacea species and alkamides inhibit prostaglandin E(2) production in RAW264.7 mouse macrophage cells.  J Agric Food Chem. 2007;  55 7314-22
• 122 Hamer R R, Tegeler J J, Kurtz E S, Allen R C, Bailey S C, Elliott M E. et al . Dibenzoxepinone hydroxylamines and hydroxamic acids: dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity.  J Med Chem. 1996;  39 246-52
• 123 Suzuki T, Miyata N. Non-hydroxamate histone deacetylase inhibitors.  Curr Med Chem. 2005;  12 2867-80
• 124 Cravatt B F, Lichtman A H. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system.  Curr Opin Chem Biol. 2003;  7 469-75
• 125 Lin S, Khanolkar A D, Fan P, Goutopoulos A, Qin C, Papahadjis D. et al . Novel analogues of arachidonylethanolamide (anandamide): affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability.  J Med Chem. 1998;  41 5353-61
• 126 Chen Y, Fu T, Tao T, Yang J, Chang Y, Wang M. et al . Macrophage activating effects of new alkamides from the roots of Echinacea species.  J Nat Prod. 2005;  68 773-6
• 127 Baldwin G C, Tashkin D P, Buckley D M, Park A N, Dubinett S M, Roth M D. Marijuana and cocaine impair alveolar macrophage function and cytokine production.  Am J Respir Crit Care Med. 1997;  156 1606-13
• 128 Klein T W. Cannabinoid-based drugs as anti-inflammatory therapeutics.  Nat Rev Immunol. 2005;  5 400-11
• 129 Klein T W, Newton C, Widen R, Friedman H. Delta 9-tetrahydrocannabinol injection induces cytokine-mediated mortality of mice infected with Legionella pneumophila. .  J Pharmacol Exp Ther. 1993;  267 635-40
• 130 Kishimoto S, Kobayashi Y, Oka S, Gokoh M, Waku K, Sugiura T. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL-60 cells.  J Biochem. 2004;  135 517-24
• 131 Sasagawa M, Cech N B, Gray D E, Elmer G W, Wenner C A. Echinacea alkylamides inhibit interleukin-2 production by Jurkat T cells.  Int Immunopharmacol. 2006;  6 1214-21
• 132 Greger H. Comparative phytochemistry of alkamides. Amsterdam, Oxford, New York; Elsevier 1988
• 133 Bryant B P, Mezine I. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons.  Brain Res. 1999;  842 452-60
• 134 Sugai E, Morimitsu Y, Iwasaki Y, Morita A, Watanabe T, Kubota K. Pungent qualities of sanshool-related compounds evaluated by a sensory test and activation of rat TRPV1.  Biosci Biotechnol Biochem. 2005;  69 1951-7
• 135 Turner R B, Bauer R, Woelkart K, Hulsey T C, Gangemi J D. An evaluation of Echinacea angustifolia in experimental rhinovirus infections.  N Engl J Med. 2005;  353 341-8
• 136 Schoop R, Klein P, Suter A, Johnston S L. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis.  Clin Ther. 2006;  28 174-83
• 137 Meadows D C, Mathews T B, North T W, Hadd M J, Kuo C L, Neamati N. et al . Synthesis and biological evaluation of geminal disulfones as HIV-1 integrase inhibitors.  J Med Chem. 2005;  48 4526-34
• 138 Jia C, Shi H, Wu X, Li Y, Chen J, Tu P. Determination of echinacoside in rat serum by reversed-phase high-performance liquid chromatography with ultraviolet detection and its application to pharmacokinetics and bioavailability.  J Chromatogr B Analyt Technol Biomed Life Sci. 2006;  844 308-13
• 139 Luettig B, Steinmuller C, Gifford G E, Wagner H, Lohmann-Matthes M L. Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea. .  J Natl Cancer Inst. 1989;  81 669-75
• 140 Classen B, Thude S, Blaschek W, Wack M, Bodinet C. Immunomodulatory effects of arabinogalactan-proteins from Baptisia and Echinacea. .  Phytomedicine. 2006;  13 688-94
• 141 Bauer R. New knowledge regarding the effect and effectiveness of Echinacea purpurea extracts.  Wien Med Wochenschr. 2002;  152 407-11
• 142 Woelkart K, Marth E, Suter A, Schoop R, Raggam R B, Koidl C. et al . Bioavailability and pharmacokinetics of Echinacea purpurea preparations and their interaction with the immune system.  Int J Clin Pharmacol Ther. 2006;  44 401-8
• 143 Hostettmann K. History of a plant: the example of Echinacea.  Forsch Komplementarmed Klass Naturheilkd. 2003;  10 (Suppl 1) 9-12
• 144 Jones J D, Dangl J L. The plant immune system.  Nature. 2006;  444 323-9
• 145 de Wit P J. How plants recognize pathogens and defend themselves. Cell Mol Life Sci 2007, in press
• 146 McPartland J M, Norris R W, Kilpatrick C W. Coevolution between cannabinoid receptors and endocannabinoid ligands.  Gene. 2007;  397 126-35
• 147 McPartland J M, Matias I, Di Marzo V, Glass M. Evolutionary origins of the endocannabinoid system.  Gene. 2006;  370 64-74
• 148 Jonsson K O, Vandevoorde S, Lambert D M, Tiger G, Fowler C J. Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide.  Br J Pharmacol. 2001;  133 1263-75
• 149 Matovic N, Matthias A, Gertsch J, Raduner S, Bone K M, Lehmann R P. et al . Stereoselective synthesis, natural occurrence and CB(2) receptor binding affinities of alkylamides from herbal medicines such as Echinacea sp.  Org Biomol Chem. 2007;  5 169-74