Artemisia plants contain essential oils

Monoterpenes in Artemisia

Essential oils of Artemisia plants The essential oils of Artemisia annua have been extensively studied and the major constituents are cineole, camphene, a-pinene, germacrene, caryophyllene, camphor and artemisia ketone. They are present at concentrations of 0.20-0.25% and have shown not only different antimicrobial activities, but also anti-inflammatory and cytotoxic activities1. They are reduced by high drying temperatures of the herb. Artemisia ketone is a major constituent of some cultivars of A. annua. Like other ketones it inhibits hemozoin crystallization in malaria infected persons. Nerolidol has an IC50 of 0.99 µmol/L and may lead to 100% growth inhibition at the schizont stage. Their concentration in Artemisia annua vary with plant development M L Towler and P. Weathers Industrial Crops and Products, Variations in key artemisinin and other metabolites throughout plant development in Artemisia annua L for potential therapeutic use,2015, 1 :67 ; 1885-191. α-Pinene is a volatile constituent present in the plant regardless of origin at levels up to 0.05% of dry weight Bhakuni RS, Jain DC, Sharma, RP, Kumar S (2001) Secondary metabolites of Artemisia annua and their biological activity. Curr Sci 80:35-48 Seatholo ST (2007) The biological activity of specific essential oil constituents. Thesis for MS in Medicine, Univ Witwatersrand, So. Africa Song HX, Xie Y, Ye YP Advances in saponin-based adjuvants. Vaccine (2009) 27:1787-1796 In a South African study, which determined the antimalarial activity of 20 essential oils, α-pinene ranked second with an IC50 of 1.2 µM, similar to that of quinine at 0.29 µM 1,8-Cineole (eucalyptol) often comprises up to 30% of the essential oil in A. annua or 0.24-0.42 % (V/DW) Su V, King D, Woodrow I, McFadden G, Gleadow R (2008) Plasmodium falciparum growth is arrested by monoterpenes form eucalyptus oil. Flavour Frag J 23:315-318 Charles DJ, JE Simon, Wood KV, Heinstein P Germplasm variation in artemisinin content of Artemisia annua using an alternative method of artemisinin analysis from crude plant extracts. J. Nat. Prod. (1990) 53:157–160. The molecule is a strong inhibitor of the pro-inflammatory cytokines TNFα, IL-6 and IL-8. Juergens UR, Engelen T, Racké K, Stöber M, Gillissen A, Vetter H (2004) Inhibitory activity of 1.8cineol (eucalyptol) on cytokine production in cultured human lymphocytes and monocytes. Pulmon Pharmacol Therapetu 17:281-287 Growth and development of chloroquine-resistant and chloroquine-sensitive Plasmodium strains are affected and are stalled at the early trophozoite stage. This volatile terpene is rapidly absorbed into the blood when delivered either orally or as an inhalant Kovar K, Gropper B, D. Friess D, Ammon HPT (1987) Blood levels of 1,8-cineole and locomotor activity of mice after inhalation and oral administration of rosemary oil. Planta Medica 53:315-318. Stimpfl T, Nasel B, Nasel C, Binder R, Vycudilik W, Buchbauer G. Concentration of 1,8-cineol in human blood during prolonged inhalation. Chem. Senses (1995) 20:349-350 reaching 15 µg mL-1 in 60 min (Kovar et al. 1987) suggesting its possible use as an antimalarial inhalant. With an IC50 of 0.02 mg mL-1 and an LD50 of ~25 mg mL-1, either inhalation or oral delivery is reasonable Kengne RDC (2010) Caracterisation physico-chimique de Artemisia annua (asteraceae), plante medicinale cultivee au Cameroun. MS thesis in Organic Chemistry, Univ de Dschang Republic of Cameroon Artemisia ketone is a major constituent of A. annua often up to 60 %. The name given to artemisia ketone may be misleading. It is a small linear molecule which is not parent of heavier molecules with several rings like artemisinic acid, arteannuin B or artemisinin. A lot of research work has been devoted to other constituents like artemisinin, scopoletine, limonene, eucalyptol, borneol, luteolin, eupatin, casticin, but artemisia ketone is completely absent in the scientific literature. The molecule had been discovered in Artemisia annua in 1938 Walter A. Jacobs and Robert C. Elderfield. The Terpenes, Saponins, and Closely Related Compounds. Annual Review of BiochemistryVol. 7: 449-472 (Volume publication date July 1938) DOI: 10.1146/annurev.bi.07.070138.002313 but then fell into oblivion. A recent paper from Serbia Niko Radulović, Pavle Randjelovic, Toxic essential oils. Part II: Chemical, toxicological, pharmacological and microbiological profiles of Artemisia annua L. volatiles. Food and chemical toxicology: 2013, 58, 37-49 DOI: 10.1016/j.fct.2013.04.016 · shows that artemisia ketone has a stronger free radical scavenging effect and a stronger antimicrobial activity than other well known monoterpenes in Artemisia annua. It is important also to remember that thujone is a ketone with strong antimalarial properties and is present in significant concentrations in most artemisia species. Our interest was further raised when we read in another recent paper ketones also can reduce pain and inflammation. Ruskin DN, Kawamura M, Masino SA. Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet. PLoS One. 2009 Dec 23;4(12):e8349. It may also play a role in hemozoin formation. Plasmodium needs hemoglobin for its survival and multiplication in merozoites inside the red blood cell. Although this gives the parasite access to nitrogen, it leaves debris like heme, which is toxic. The parasite circumvents this by causing oxidation of Fe(II) in heme to Fe(III) forming hematin that polymerizes into an insoluble product called β-hematin and haemozoin, which is nontoxic to the parasite and inhibits cell-mediated immunity against the parasite. Other ketones like curcumin were implicated as inhibitors of β-hematin synthesis, so it is possible that artemisia ketone plays a similar role. Limonene is part of the so called “cineole cassette”, which include 1,8-cineole, limonene, myrcene, αpinene, β-pinene, sabinene and α-terpineol. Raguso RA, Levin RA, Foose SE, Holmberg MW, Mc Dade LA (2003) Fragrance chemistry, nocturnal rhythms and pollination, syndromes’ in Nicotiana. Phytochemistry 63:265–284 many of which affect particular stages of Plasmodium species. Limonene, for example, arrests isoprenoid biosynthesis in Plasmodium Goulart H R, Kimura E A, Peres V J, Couto A S, Aquino Duarte F A, Katzin A M Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum. Antimicrob Agents Chemother (2004) 48: 2502-9 and development at the ring and trophozoite stages Moura IC, Wunderlich G, Uhrig ML, Couto AS, Peres VJ, Katzin AM, Kimura EA (2001) Limonene arrests parasite development and inhibits isoprenylation of proteins in Plasmodium falciparum Antimicrob. Agents Chemother 45:2553-2558 while 1,8-cineole affects the trophozoite stage. Limonene also inhibits protein isoprenylation in P. falciparum, arresting parasite development within 48 h of treatment The in vitro IC50 against Plasmodium in these trials was 2.27 mM, significantly below 15.5 mM that was previously shown in vivo in patients with advanced cancer. The pharmacokinetics is favorable; limonene and its metabolites remain in the plasma for at least 48 hrs Miller JA, Hakim IA, Chew W, Thompson P, Chew W, Thomsen CA, Chow HHS (2010) Adipose tissue accumulation of d-limonene with the consumption of a lemonade preparation rich in d-limonene content. Nutrition Cancer 62:783-788. This is important for the elimination of gametes and malaria transmission. A combination of essential oils may enhance the antimalarial effect of artesunate and even reverse the resistance of P. berghei against artesunate. Liu AR, Yu ZY, Lu LL, Sui ZY (2004) The synergistic action of guanghuoxiang volatile oil and sodium artesunate against Plasmodium berghei and reversal of SA-resistant Plasmodium berghei, Chin J Parasitol Parasitic Diseases 18:76-78 The concentration of monoterpenes is higher in the pre-flowering phase, but is reduced by high drying temperature. Khangholil S, Rezaeinodehi A (2008) Effect of drying temperature on essential oil content and composition of sweet wormwood (Artemisia annua) growing wild in Iran. Pak J Biol Sci 11:934-937 Ferreira JFS, Luthria DL (2010) Drying affects artemisinin, dihydroartemisinic acid, artemisinic acid, and the antioxidant capacity of Artemisia annua L. leaves J. Agric. Food Chem. 2010, 58, 1691–1698 The monoterpene limonene has a very favourable toxicity profile and is easily available at low prices. Limonene is also present in A. annua at concentrations up to 7 mg kg-1 Bhakuni RS, Jain DC, Sharma, RP, Kumar S (2001) Secondary metabolites of Artemisia annua and their biological activity. Curr Sci 80:35-48 So far, studies have concentrated on this particular monoterpene, but others like eucalyptol, present in the essential oil of Artemisia plants, might have a similar detrimental action on the apicoplast, a non-photosynthetic plastid of most apicomplexan parasites, such as Plasmodium. The sesquiterpene nerolidol, found in Artemisia species arrests development of the intraerythrocytic stages of the parasite. It has an antiplasmodial IC50 of 0.99 µM compared to that of 533 µM for limonene Van Zyl, Robyn L.; Seatlholo, Sammy T.; Van Vuuren, Sandy F.; Viljoen, Alvaro M. The Biological Activities of 20 Nature Identical Essential Oil Constituents. Journal of Essential Oil Research . Jul/Aug 2006 Supplement, Vol. 18, p129-133. Seatholo ST, The biological activity of specific essential oils constituents. Thesis for MS in Science, Univ Witwaterstrand South Africa. 2007. Indians of the Amazon basin in Brazil use the vapors of the leaves of Viola surinamensis to treat malaria and the sesquiterpene nerolidol was identified as the active constituent leading to 100 % growth inhibition at the schizont stage Lopes NP, Kato MJ, Andrade EH de A, Maia JGS, Yoshida M, Planchart AR, Katzin AM (1999) Antimalarial use of volatile oil from leaves of Virola surinamensis (Rol.) Warb. By Waipãpi Amazon Indians. J Ethnopharmacol 67:313-319 Like limonene nerolidol may affect the isoprenoid pathway in the apicoplast of Plasmodium. Nerolidol concentrations vary with the origin of A. annua. The highest value was found in A. annua from Ethiopia Muzemil A (2008) Determination of artemisinin and essential oil contents of Artemisia annua L. grown in Ethiopia and in vivo antimalarial activity of its crude extracts against Plasmodium berghei in mice. MS Thesis in Medicinal Chemistry, Addis Ababa University, Ethiopia. Nerolidol was also found to be higher in the stems than in the leaves of A. annua Li QG, Peggins JO, Fleckenstein LL, Masonic K, Heiffer MH, Brewer TG (1998) The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol 50:173-182 But the bioavailabilty of monoterpenes per os is low. Moxa or inhalation is more appropriate for administration. In human volunteers for alpha-pinene absorbed by inhalation only 0.001% is eliminated by urine. The main part accumulates in adipose tissues and is released progressively into blood Falk AA, Hagberg MT, Löf AE, Wigaeus-Hjelm EM, Wang ZP Uptake, distribution and elimination of alpha-pinene in man after exposure by inhalation. Scand J Work Environ Health. 1990 Oct;16(5):372-8 The results of a study in Austria showed that 1,8-cineol is well absorbed from breathing air, with a peak plasma concentration after 18 min. The elimination of this fragrance compound from the blood is biphasic, with a mean distribution half-life of 6.7 min and an elimination half-life of 104.6 min. W. Jager, B. NaJel, C. NaSel1, R. Binder, T. Stimpfl, W. Vycudilik and G. Buchbauer. Pharmacokinetic Studies of the Fragrance Compound 1-8-Cineol in Humans during Inhalation. Chem. Senses 21: 477-480, 1996. Terpene content for milk samples is characterized by the same terpenes as those added to food. The terpenes appear to be transferred unaltered into the milk. Volatile terpenes in essential oils, which could influence milk flavor, are transferred into milk via both gastrointestinal and respiratory exposure. Most of it is probably absorbed by inhalation of pinenes emitted by plants or trees. Among all monoterpenes emitted by trees alpha-pinene has on the average the highest percentage. Sophie MOUKHTAR, Impact des émissions naturelles sur les épisodes de pollution photochimique. Application à la region du fossé rhénan Institut National Polytechnique de Toulouse. Thèse. 2005 Primary agents of the tree's defense are monoterpenes, aromatic molecules such as pinenes. Pinenes and limonene from Artemisia arborescens also display antiviral properties by inactivating viruses and inhibiting cell-to-cell diffusion. Adorjan, Barbara (2010) Biological properties of essential oils. Diplomarbeit, University of Vienna. Fakultät für Lebenswissenschaften They increase the activity of human natural killer cells. Li Q, Kobayashi M, Inagaki H, Hirata Y, Li YJ, Hirata K, Shimizu T, Suzuki H, Katsumata M, Wakayama Y, Kawada T, Ohira T, Matsui N, Kagawa T. A day trip to a forest park increases human natural killer activity and the expression of anti-cancer proteins in male subjects. J Biol Regul Homeost Agents. 2010 Apr-Jun;24(2):157-65. The Japanese call it a forest bathing trip. Pinenes have strong antimicrobial properties. Aristides Medeiros Leite, Edeltrudes de Oliveira Lima , Evandro Leite de Souza, Margareth de Fátima Formiga Melo Diniz, Vinícius Nogueira Trajano. Inhibitory effect of β-pinene, α-pinene and eugenol on the growth of potential infectious endocarditis causing Gram-positive bacteria. Revista Brasileira de Ciências Farmacêuticas. vol. 43, n. 1, jan./mar., 2007 These molecules also have immunostimulating, anti-inflammatory and gastroprotective properties. DK Lima. Evaluation of the Antinociceptive, Anti-Inflammatory and Gastric Antiulcer Activities of the Essential Oil From Piper Aleyreanum C.DC in Rodents. J Ethnopharmacol 142 (1), 274-282. 2012 May 12.

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