Plant essential oils and formamidines as insecticides/ acaricides:what are the molecular targets?
Wolfgang B LENAU1,Eva R ADEMACHER2,Arnd B AUMANN3
1Institut für Bienenkunde(Polytechnische Gesellschaft),Goethe-Universität Frankfurt am Main,
Karl-von-Frisch-Weg2,61440Oberursel,Germany
2Institute of Biology,Freie Universität Berlin,14195Berlin,Germany
3Institute of Complex Systems—Cellular Biophysics-(ICS-4),Forschungszentrum Jülich,52425Jülich,Germany
Received16May2011–Revised29August2011–Accepted21October2011
Abstract–The parasitic mite Varroa destructor is the main cause of the severe reduction in beekeeping during the last few decades.Therefore,efforts have been made to develop chemical treatments against the parasite.In the past,synthetic products were preferentially used to combat Varroa mites.Nowadays,mainly plant essential oils and organic acids are applied because they are safer and impose less unfavorable effects on the environment.Essential oils contain mixtures of most
ly volatile and odorous terpenoid constituents.The molecular targets of these substances are tyramine and/or octopamine receptors that control and modulate vital functions ranging from metabolism to behavior.Disturbing the native function of these receptors in the mite results in deleterious effects in this parasite.This overview considers not only tyramine and octopamine receptors but also other potential targets of essential oils including ionotropic GABA A receptors,TRP type ion channels,and acetylcholinesterase.
GABA/G protein-coupled receptor/octopamine/thymol/tyramine
1.PLANT ESSENTIAL OILS—
AN INTRODUCTION
The availability of environmentally safe and efficient chemicals against arthropod pests is an important aspect for veterinary and crop industries.At present,chemical compounds that rapidly deliver their insecticidal effect are preferentially used to achieve a timely reduction of pests and ectoparasites on their respective hosts.This condition is fulfilled by compounds that modify the activity of voltage-gated and/or ligand-gated ion channels in the central nervous system(CNS)and by compounds that impair the activity of neuronal enzymes such as acetylcholinesterase(AChE)or that
manipulate the overall metabolic status of the parasite (for a review,see Isman2006).Substances such as synthetic pyrethroids inhibit voltage-gated sodium channels that are important for the firing of neuronal action potentials.Phenyl-pyrazolines or ,lindane) block the activity of GABA A channels,important members of the ligand-gated ion channel family involved in inhibitory signal generation in neurons.Organophosphates inhibit the enzymatic activity of AChE,an enzyme controlling the concentration of the excitatory neurotransmitter acetylcholine(ACh)in the synaptic cleft.Iso-flavonoids such as rotenone poison mitochondria and thus cause the breakdown of cellular energy production.Metabotropic(G protein-coupled) octopamine receptors are the target of formami-dine pesticides such as amitraz which
manipulate Corresponding author:W.Blenau,
Blenau@bio.uni-frankfurt.de
Manuscript editor:Bernd Grünewald
Apidologie Review article *INRA,DIB and Springer-Verlag,France,2011
DOI:
10.1007/s13592-011-0108-7
cellular signal transduction processes.Despite the efficient and wide use of these substances,they seem to harbor certain disadvantages.(1)Parasites can develop resistance to the chemicals,probably because the generation times of the arthropod pests are short.(2)Cross-reactivity of such substances might also be significant in beneficial insects such as the honeybee.In addition,these substances might cause undesired allergic or toxic effects in humans.For such reasons,there is a continual demand for compounds that,on the one hand,efficiently reduce parasites or pests and,on the other hand,are safe for the host,the environment,and non-target species,including man,that come into contact with such insecti-cides/acaricides.Over the years,plant essential oils have been considered as an attractive alterna-tive that might fulfill these criteria.
Plant essential oils are complex mixtures of odorous substances obtained from botanical raw materia
ls by water vapor extraction,dry distil-lation,or mechanical treatment without heating (Isman2006;Vigan2010).Because of their odorous character,plant essential oils are widely used as fragrances and flavorings in perfume and food industries.To identify and to further characterize the individual components of es-sential oils,either separation by gas chromatog-raphy or HPLC has to be performed.These analyses have identified monoterpenes,sesqui-terpenes,and related aromatic compounds as the main constituents of plant essential oils.Terpe-noids are derived from five-carbon isoprene units.Coupling of two isoprene units leads to ten-carbon structures known as monoterpenoids, whereas coupling of three isoprene units leads to sesquiterpenoids(Table I).Terpenoids can be linear(acyclic)or contain cyclic structures (Table I).Further biochemical modifications by endogenous plant enzymes can cause oxidation, rearrangement,or additional cyclization(Table I) that increases the variability of essential oil constituents(Chappell1995;Holstein and Hohl 2004).At approximately90%,the mono-and sesquiterpenoids outnumber the other constitu-ents of plant essential oils.Nevertheless,some aromatic compounds are worth mentioning (Table I).
Similar to their heterogeneous composi-tion,plant essential oils display a broad spectrum of biological activity.They can be toxic for insects and microbes,but can also act as insect antifeedants and repellents (Anthony et al.2005;Isman2006;Nerio et al.2010;Vigan2010).The toxic effect of essent
ial oils is most likely mediated by neurological mechanisms.Indeed,plant essen-tial oils have been suggested to exert their bioactivity by interacting with various molec-ular targets including tyramine and octop-amine receptors(Enan2001,2005a,b;Price and Berry2006),ionotropic GABA receptors (Priestley et al.2003;Tong and Coats2010), and AChE(Grundy and Still1985;Ryan and Byrne1988;Keane and Ryan1999).As previously mentioned,octopamine receptors have also been identified as a target site of the formamidine class of insecticides(Evans and Gee1980;Gole et al.1983;Downer et al. 1985;Dudai et al.1987;Chen et al.2007).
In mammalian tissues,p-tyramine,β-phenylethylamine,tryptamine,and octopamine are present at very low(nanomolar)concen-trations and are therefore referred to as“trace amines.”Trace amine-associated receptors (TAARs)have recently been discovered in mammals(for a review,see Zucchi et al. 2006).It is worth emphasizing,however,that thus far,only two members of the TAAR family have been shown to be responsive to trace amines.In addition,mammalian TAARs are not closely related to arthropod tyramine and octopamine receptors.Thus,it appears that in mammals,TAARs evolved independently from the arthropod tyramine and octopamine receptors and acquired the ability to interact with different amines,including the decar-boxylated thyroid hormone derivatives known as thyronamines,several volatile amines,and possibly other as yet unidentified endogenous compounds
(for a review,see Zucchi et al. 2006).Therefore,arthropod tyramine and octopamine receptors might emerge as prom-ising targets for insecticides/, plant essential oil components)with no or low toxicity in vertebrates.
W.Blenau et
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Table I.Naturally occurring essential oil components and synthetic substances mentioned in the text. Compound Molecular
formula
Substance class Sources(examples)
Linalool[licareol=(R)-(−)-linalool;coriandrol=(S)-(+)-linalool]C10H18O Monoterpenoid alcohol,
linear
Coriandrum sativum
(coriander)
Ocimum basilicum(basil)
Citrus×sinensis(sweet
orange)
Citral[geranial=citral A; neral=citral B]C10H16O Monoterpenoid aldehyde,
linear
Backhousia citriodora
(lemon myrtle)
Cymbopogon spp.
(lemongrass)
Leptospermum liversidgei
(lemon tea tree)
Menthol C10H20O Monoterpenoid alcohol,
monocyclic,unsaturated Mentha×piperita (peppermint)
α-Terpineol C10H18O Monoterpenoid alcohol,
monocyclic,unsaturated Melaleuca leucadendra (cajuput oil)
Pinus spp.(pine oil) Citrus×aurantium (petitgrain oil)
Carveol C10H16O Monoterpenoid alcohol,
monocyclic,unsaturated cis-(−)-Carveol:
Mentha spicata(spearmint)
Pulegone C10H16O Monoterpenoid ketone,
monocyclic Nepeta cataria(catnip) Mentha×piperita
(peppermint) Mentha pulegium (pennyroyal)
R-(−)-Carvone,S-(+)-carvone C10H14O Monoterpenoid ketone,
monocyclic,unsaturated
S-(+)-carvone
Carum carvi(caraway)
Anethum graveolens(dill)
R-(−)-carvone
Mentha spicata(spearmint)
α-Terpinene,g-terpinene C10H16Monoterpenoid,monocyclic,
unsaturated Melaleuca alternifolia
(tea tree oil)
Citrus×limon(bergamot oil)
p-Cymene C10H14Monoterpenoid,monocyclic,
aromatic Cuminum cyminum(cumin) Chenopodium ambrosioides
(epazote)
Peumus boldus(boldo)
Carvacrol C10H14O Monoterpenoid phenol Origanum vulgare(oregano)
Thymus spp.(thyme)
Lepidium spp.(pepperwort)
Thymol C10H14O Monoterpenoid phenolic
derivative of cymene Thymus spp.(thyme) Trachyspermum copticum
(ajwain)
Origanum vulgare(oregano)
Anethole(para-methoxyphenylpropene,C10H12O Monoterpenoid ether,
aromatic,unsaturated
Pimpinella anisum(anise)
Foeniculum vulgare(fennel) Molecular targets of plant essential
oils
Table I continued.
Compound Molecular
formula
Substance class Sources(examples)
p-propenylanisole, isoestragole)Syzygium anisatum (anise myrtle)
Eugenol C10H12O2Monoterpenoid,methoxy-phenol,
unsaturated Syzygium aromaticum (clove oil)
Pimenta dioica(allspice) Myristica fragrans(nutmeg)
(+)-Camphor,(−)-camphor C10H16O Monoterpenoid ketone,
bicyclic (+)-Camphor Cinnamomum camphora
(camphor laurel) Rosmarinus officinalis (rosemary)
(−)-Camphor Tanacetum parthenium (feverfew)
Matricaria recutita (German chamomile)
α-Pinene;β-pinene C10H16Monoterpenoid,bicyclic,
unsaturated Pinus spp.(pine resin) Rosmarinus officinalis
(rosemary)
(+)-Borneol C10H18O Monoterpenoid ketone,
bicyclic Cinnamomum camphora (camphor oil) Coriandrum sativum (coriander) Tanacetum vulgare(tansy)
Bornyl acetate C12H20O2Acetic acid ester of borneol Abies spp.(fir)
Pinus spp.(pine)
Picea spp.(spruce)
Eucalyptol(1,8-cineol,1, 8-cineole,cineol,cineole)C10H18O Monoterpenoid,
oxa-bicyclic
Eucalyptus spp.
(eucalyptus oil)
Cinnamomum camphora
(camphor laurel)
modulate
Laurus nobilis(bay leaf)
Farnesol C15H26O Sesquiterpene,linear Cymbopogon spp.
(lemongrass,citronella oil)
Citrus×aurantium(bitter
orange,neroli oil)
Polianthes tuberosa
(tuberose)
Cinnamic alcohol C9H10O Aromatic,unsaturated
alcohol Liquidambar orientalis (storax)
Myroxylon balsamum (balsam Peru) Cinnamomum spp. (cinnamon)
Cinnamaldehyde C9H8O Aromatic,unsaturated aldehyde Cinnamomum spp.
(cinnamon)
Capsaicin C18H27NO3Capsaicinoid,8-methyl-Capsicum spp.(chili pepper)
W.Blenau et
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2.USE OF PLANT ESSENTIAL OILS
FOR VARROA TREATMENT
OF HONEYBEE COLONIES The honeybee,Apis mellifera,pollinates about80%of crop and wild plants.This makes it the fourth most important farm animal in Germany(after cattle,pigs,and poultry).Hence, it is alarming that the honeybee stocking density has rapidly declined over the last few decades. One reason for this dramatic reduction in beekeeping is the parasitic mite Varroa destructor, which was introduced into Germany in the 1970s.V.destructor can only reproduce in a honeybee colony,precisely in sealed brood cells. It attaches to the body of the larva,pupa,or adult bee and weakens its host by sucking hemolymph (for reviews,see Rademacher1990;Sammataro et al.2000;Rosenkranz et al.2010).The mite acts as a vector and spreads RNA viruses such as deformed wing virus to the bee(for reviews,see Genersch and Aubert2010;Le Conte et al. 2010).A significant mite infestation will lead to the death of the honeybee colony,usually during the summer or winter months.V.destructor is the parasite with the most pronounced economic impact on the beekeeping industry.It is a major contributing factor to colony collapse disorder (CCD)and to non-CCD winter losses,which constitute severe problems in beekeeping world-wide(Vanengelsdorp et al.2009;Guzman-Novoa et al.2010;for a review,see Le Conte et al.2010).Honeybees in CCD colonies are characterized by higher pathogen loads and are co-infected with a greater number of pathogens
compared with control populations,suggesting an interaction between pathogens and other stress factors in CCD and a possible legacy effect of Varroa parasitism(V anengelsdorp et al.2009).
Numerous efforts have been made to develop chemical treatments against V.destructor (Mutinelli and Rademacher2003;Rosenkranz et al.2010).Nowadays,products based on organic ,formic acid and oxalic acid; Rademacher and Imdorf2004;Rademacher and Harz2006;Calderone2010),essential oils (e.g.,thymol;Imdorf et al.1995,1999; Rademacher and Radtke2001;Floris et al. 2004),,fluvalinate and flu-methrin),,coumaphos; Milani and Lob1998),and , amitraz;Floris et al.2001)are used to treat infected colonies.Essential oils(and formami-dines)most probably exert their therapeutic effects by binding to tyramine and/or octopamine receptors.Amongst others,, Apiguard and Thymovar)and combinations of thymol and other essential oils such as eucalyptol,camphor,and ,Api Life VAR)are also used for Varroa treatment (Imdorf et al.1999)and have been approved as veterinary drugs in many European countries. Calderone and Spivak(1995)found that a blend of natural products similar to Api Life VAR provided more than98.5%control of V. destructor.In a recent study,Ghasemi et al. (2011)determined the fumigant toxicity of essential oils taken from Thymus kotschyanus,
Table I continued.
Compound Molecular
formula
Substance class Sources(examples)
N-vanilyl-6-nonenamide,
aromatic
Chlordimeform C10H13ClN2Amidine,organochloride Synthetic
Demethylchlordimeform C9H11ClN2Amidine,organochloride,
aromatic Synthetic
Amitraz C19H23N3Amidine,triazapentadiene,
aromatic
Synthetic
For each substance,the molecular formula,characteristic structural properties,and a selection of natural sources synthesizing the compound are given
Molecular targets of plant essential
oils

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