Essential Oils Components as a New Path to Understand Ion Channel

7/29/2019 Essential Oils Components as a New Path to Understand Ion Channel

1/5

Minireview

Essential oils components as a new path to understand ion channelmolecular pharmacology

Demetrius Antonio Machado de Arajo a, Christiane Freitas b, Jader Santos Cruz b,a Laboratrio de Tecnologia Farmacutica, Universidade Federal da Paraba, Mail Box 5009, CEP: 58051-970, Joo Pessoa, PB, Brazilb Departamento de Bioqumica e Imunologia, Universidade Federal de Minas Gerais, CEP: 31270-901, Belo Horizonte, MG, Brazil

a b s t r a c ta r t i c l e i n f o

Article history:

Received 20 December 2010Accepted 27 April 2011

Keywords:

Natural products

Ion channels

Terpenes

Na+ channels

Ca2+ channels

K+ channels

The discovery and development of new drugs targeting voltage-gated ion channels are important for treatinga variety of medical conditions and diseases. Ion channels are molecular nanostructures expressedubiquitously throughout the whole body, and are involved in many basic physiological processes. Over the

years, natural products have proven useful in the pharmacological assessment of ion channel structure andfunction, while also contributing to the identification of lead molecules for drug development. Essential oils

are complex chemical mixtures isolated from plants which may possess a large spectrum of biologicalactivities most of them of clinical interest. Among their bioactive constituents, terpenes are small to medium-sized components and belong to different chemical groups. Various reports have drawn our attention to the

fact that terpenes are novel compounds targeting voltage-gated ion channels. The purpose of this review is to

provide a focused discussion on the molecular interaction between monoterpenes and phenylpropenes withvoltage-gated ion channels in different biological scenarios.

2011 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540Essential oils: new source for new molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541Constituents of essential oils that acts in the central and peripheral nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541

Pitfalls and promises in the field . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

Introduction

Ion channels are integral membrane proteins designed to catalyze

ion flux and, as a consequence produce changes in the membranepotential. These molecular nanostructures are present in all types ofcells but they have a very important role in excitable cells where theyare the main actors responsible for the generation of action potentials.

Action potentials are the result of the activity of many different typesof ion channels working in concert to carry information from one cellto another in a very controlled way.

There is much information available about the function of ion

channels (Catterall 2010). Usually, we separate ion channels in two

major super-families, voltage-dependent and ligand-dependent ionchannels.

They are involved in a plethora of distinct physiological processes

such as: neurotransmitter release, excitationcontraction coupling,excitationtranscription coupling, control of gene expression, celldevelopment and so on. Therefore, we can argue that the normal ionchannels' activity (or function) is crucial for the maintenance of

health. Another important point is the realization that ion channeldysfunctions could lead to serious pathological disorders compromis-ing the whole organism. In 2006 the US Drug Administrationapproved 18 new molecular compounds and two of them had their

primary mode of action attributed to ion-channel modulationindicating that ion channels are very attractive and promising drugdiscovery targets (Dunlop et al., 2008).

In this way one would think that these molecular bio-structures

are important pharmacological targets for natural-based chemical

Life Sciences 89 (2011) 540544

Corresponding author. Tel.: +55 31 3409 2668; fax: +55 31 3409 2613.

E-mail addresses: [email protected], [email protected] (J.S. Cruz).

0024-3205/$ see front matter 2011 Elsevier Inc. All rights reserved.

doi:10.1016/j.lfs.2011.04.020

Contents lists available at ScienceDirect

Life Sciences

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i f e s c i e
http://dx.doi.org/10.1016/j.lfs.2011.04.020http://dx.doi.org/10.1016/j.lfs.2011.04.020http://dx.doi.org/10.1016/j.lfs.2011.04.020mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.lfs.2011.04.020http://www.sciencedirect.com/science/journal/00243205http://www.sciencedirect.com/science/journal/00243205http://dx.doi.org/10.1016/j.lfs.2011.04.020mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.lfs.2011.04.020


2/5

compounds looking at the development of new therapeutic strategies.In order to validate this saga, highly selective and potent antagonistsor even agonists are a prerequisite (Bulaj 2008).

Drug discovery efforts posed by the medicinal chemists' commu-

nity have discovered a rather small number of molecules thatmodulate ion channels function. Taking all of that in mind, theunderstanding of how these molecules actually interacts with ion

channels are of great interest. Consequently, electrophysiological

techniques are extremely useful for the characterization of thebiological activity of isolated compounds. Electrophysiological ap-proaches are enormously rich in terms of acquired information and

have been considered as the gold-standard assay.

Essential oils: new source for new molecules

In search for new sources of natural molecules that modulate ion

channel behavior, essential oils are both promising and challenging.Plant essential oils are typically composed of volatile aromaticterpenes and phenylpropanoids. These lipophilic substances areclassified as monoterpenes and sesquiterpenes based on the number

of isoprene units (two and three respectively) besides the phenyl-propanoids, which are made up of C6C3 units. These molecules freelycross cellular membranes and may serve various signaling rolesinside the cell. In addition, there are some reports indicating that

essential oil plant components are active towards ion channels andreceptors (Gonalves et al., 2008; de Almeida et al., 2008; Alves et al.,2010). Apart from rational drug design and novel synthetic efforts,natural products are still been investigated for novel chemical

structures that may interact with known and unknown pharmaco-logical targets. The pharmacology of ion channels has become acomplex research area and as far as we understand the mechanismscontrolling ion channel functioning, more potential drug targets are

being disclosed.At this point it is worth to remind that over the decades, natural

products have undoubtedly contributed to the development of newdrugs currently used in clinical practice. More importantly, these

remarkable molecules have also been important tools for the

discovery of new pharmacological targets such as receptors and/orion channels (Vriens et al., 2008). One of the most relevant examplesis the transient receptor potential (TRP) family of ion channels. This

area is very active and there are excellent reviews covering variousaspects including the role of natural products in the discovery andpharmacological characterization of TRP channels (for review seeCalixto et al., 2005; Vriens et al., 2008) and therefore we will not cover

in detail this topic.In this mini-review we will focus on medicinal compounds which

modulate ion channels present in different physiological systems.

Constituents of essential oils that acts in the central and peripheral

nervous system

The potential use of essential oils as modulators of ion channels inthe treatment of several diseases is indeed exciting. Although most ofthe published studies quote the popular use of essential oils in thetreatment of several nervous system disorders, just a few studies

(approximately 3% in a PUBMED search) described the activity andtoxic effects of its majorcomponents on the nervous system (de Sousaet al., 2006; Goncalves et al., 2010). Only a small fraction of thosestudies deals with the interaction between terpenes and ion channels.

Linalool is a monoterpene that has been the subject of a number ofstudies and it is one of the major constituents of several essential oilsisolated from different plant species. Linalool has been reported tohave diverse biological and pharmacological activities (Celik and

Ozkaya, 2002; Peana et al., 2002; Bickers et al., 2003; de Almeida et al.,2009). There are reports showing that linalool acts on the central

nervous system but through a yet unrevealed mechanism. Linalool

shares high lipid solubility with other lipid soluble odorants that

directly affect ion channels activity (Kawai et al., 1997; Kawai, 1999;Kawai and Miyachi, 2000) suggesting that linalool could interact withcertain types of ion channels by changing the lipid membraneenvironment. It was already been described that this monoterpene

has sedative effects in vertebrates includinghumans (Buchbauer et al.,1991; Sugawara et al., 2000), and that the inhalation of linalool canlead to a significant reductionof motility in mice(Jirovetz et al., 1991).

Other possible applications for linalool are as pain modulator,anticonvulsant, hypnotic and hypothermic agent. Elisabetsky et al.(1995) described that linalool inhibits glutamatergic neurons andlater Sugawara et al. (2000) observed that it also affected human brainbeta waves amplitude. Earlier studies in newt olfactory receptor cells,

newt retinal neurons and rat cerebellar Purkinje cells demonstratedthat linalool non-selectively but reversibly suppressed the voltage-gated currents (Narusuye et al., 2005). In the same report it wasshown that linalool reduced KCl-induced intracellular Ca2+ elevationwithout affecting the machinery responsible for intracellular Ca2+

signaling (Narusuye et al., 2005).The pharmacological effects of linalool on somaticsensory neurons

have been studied in more detail by Leal-Cardoso's group (Leal-Cardoso et al., 2010). The authors provided a reasonable number ofexperimental findings to conclude that inhibition of the voltage-gatedNa+ channels is probably the major mechanism by which the

neuronal excitability is impaired.Taken all together, we may suggest a possible mechanism of action

that could be attributed to linalool as a main frame to explain itsvarious effects. As a consequence of a significant reduction in Ca2+

influx there is an important neurotransmitter release inhibition in thepresynaptic terminals. Similarly, but not independently, linalool couldelicit a blockade of voltage-gated Na+ channels causing a prematuretermination of the action potential generation which per se wouldlead to diminution of neurotransmitter release by exocytosis.

Presumably, the body of evidences in the literature support thegeneral mechanism pointed out above but it is clear that furtherstudies are necessary to explore in more detail how linalool is acting.

Eugenol, a phenylpropene derivative, is widely usedin dentistry as

local anesthetic, analgesic, anti-microbial and anti-inflammatoryagent (Hashimoto et al., 1988; Ohkubo and Kitamura, 1997; Pizzoet al., 2006). In a series of papers from Oh's group it was postulated

that the analgesic effects of eugenol in rat dental afferent neuronscould be related to its inhibitory effect on voltage-gated Na+ channels(Park et al., 2006) and on high voltage-activated Ca2+ channels (Leeet al., 2005). Surprisingly, both effects did not require TRPV1

activation (Lee et al., 2005; Park et al., 2006). Interestingly, whenmammalian central nervous system is acutely exposed to eugenol itcauses a general depressant activity leading to sedation, reduction ofconvulsions induced by electroshock and hypothermia Dallmeier and

Carlini (1981).In fact, very little is known about eugenol's mechanism(s) of action especially in the central nervous system.

However, it is well known that eugenol blocks rat sciatic nerve

compound action potentials probably by acting on the voltage-dependent Na+ channels. At high concentrations (2 mM) and duringbrief applications eugenol blocked the action potential withoutinterfering in the resting membrane potential or membrane inputresistance. However, at low concentrations (0.6 mM) and longer

applications the authors observed a significant reduction in the inputmembrane resistance which, as discussed by the authors, raises thepossibility of a secondary effect involved in the reduction of neuronalexcitability when eugenol was present (Moreira-Lobo et al., 2010).

Elucidative studies also showed that eugenol inhibited thermalnociception and capsaicin-induced thermal hyperalgesia in orofacialarea indicating that this phenylpropene derivative could also be usedfor other pathological pain conditions (Park et al., 2009). At this point

a note of caution should be presented concerning the activation of

TRPV1 channels by eugenol which could evoke excitation of

541D.A.M. de Arajo et al. / Life Sciences 89 (2011) 540544


3/5

nociceptors even knowing that this phenomenon is rather weak whencompared to other TRPV1 agonists (for example, capsaicin).

Nav1.7, Nav1.8 and Nav1.9 are Na+channel subtypes that can be

found predominantly in nociceptive DRG neurons (Akopian et al.,

1996). There are a number of studies suggesting that their expressionand functional properties are modified following inflammation ornerve injury (Dib-Hajj et al., 1998; Cummins et al., 2007). Great effort

has been made in order to a better understanding of how eugenol

actually exerts its analgesic effect. As a consequence severalmechanisms have been proposed to explain the eugenol analgesia.Recently, a well designed study elucidating the involvement of

voltage-gated Na+ channels in the eugenol-elicited analgesia cameup. To that purpose, Cho et al. (2008) pursued a detailed kineticanalysis to investigate the effects of eugenol on tetrodotoxin-sensitive(TTX-S) and tetrodotoxin-resistant (TTX-R) Na+ currents in acutely

dissociated rat dorsal root ganglion neurons. Their findings clearlyindicate that eugenol inhibits voltage-gated Na+ currents through itsinteraction with both resting and inactivated Na+ channels. Theauthors also evaluated the recovery from inactivation for both Na+

currents. Eugenol slowed the recovery from inactivation. One possible

implication that one would expect is a decrease in neuronalexcitability leading to nerve conduction blockade. To complete theirinvestigation Cho and colleagues demonstrated that the eugenolinhibition of TTX-R and TTX-S Na+ currents did not show any

stimulation frequency dependence which is a behavior distinct fromother typical anesthetics (Hille,2001).

As we indicated above eugenol presents various pathways toprovoke analgesia. There are substantial experimental evidences thatargues in favor of the participation of voltage-gated Ca2+ channels askey elements in the transmission of pain signals (McGivern andMcDonough, 2004; Lee et al., 2005; Chung et al., 2008; Zamponi et al.,2009; Perret and Luo, 2009). Knowing that eugenol is related tocapsaicin in terms of chemical structure and that capsaicin has been

demonstrated to inhibit high voltage-gated Ca2+ channels (Petersenet al., 1989; Bleakman et al., 1990), these information combined havemotivated studies to investigate whether eugenol would interact withhigh voltage-gated Ca2+ channels.

Two studies (Lee et al., 2005; Chung et al., 2008) addressed thequestion of whether eugenol would cause an inhibitory effect on Ca2+

channels. Lee et al. (2005) used rat dental primary afferent neurons

and C2D7 cells stably expressing the human N-type Ca2+ channel.Altogether, they found that eugenol did elicit an inhibitory effect onhigh voltage-gated Ca2+ current in all neurons tested and importantlythese effects were not exclusive to capsaicin-sensitive primary

afferent neurons. What would be the implication for that? These

findings suggest that the mechanisms by which eugenol and capsaicininduced Ca2+ current inhibition might be somehow different. Further,the authors confirmed this contention by using C2D7 cells (heterol-

ogously expressing Cav 2.2 the molecular counterpart for the N-typeCa2+ channels) that do not contain endogenous TRPV1 receptor. Inthis better controlled system eugenol caused the same effects as

previously described.In 2008, Chung and colleagues using a similar experimental strategy

reported thateugenol inhibited Cav 2.3 channels (R-type Ca2+ current),

andconfirming the earlier results theinhibitory effect wasnot related tothe activation of TRPV1 receptor. The authors, based on their interesting

findings, proposed that due to the complete lack of TRPV1 involvementin eugenol's inhibitoryeffects, an analog of eugenol might be developedto substitute for capsaicin as a potential analgesic drug withoutexhibiting irritant actions (Chung et al., 2008).

In excitable cells suchas neurons, voltage-gated K+ channels serveto repolarize or hyperpolarize the membrane. Therefore, pharmaco-logical activation of K+ channels in excitable cells reduces excitability.On the other hand, K+ channels inhibition would cause an increase in

excitability. Overall, K+ channels constitute potential drug targets for

the treatment of diverse diseases from cancer to cardiovascular

disorders (Wulff et al., 2009). Eugenol has both excitatory andinhibitory effects (Lee et al., 2005; Park et al., 2006; Li et al., 2007). Theexcitatoryeffect attributed to eugenol comes to its activation of TRPV1channels that evokes an inward current capable to provoke a

membrane depolarization. This effect would possibly be the oneresponsible for the irritant actions of eugenol. However, it wasreported that eugenol inhibits voltage-gated K+ currents causing a

prolongation of the action potential (Li et al., 2007). Interestingly,

eugenol only increased the action potential duration in a smallsubpopulation of trigeminal ganglion neurons (about 13%). Theauthors raised an important issue when comparing the concentration

ranges where eugenol blocked Na+ and Ca2+ currents indicating thateugenol is less potent towards Ca2+ channels than Na+ or K+

channels. In summary, the inhibition demonstrated by Li andcolleagues is likely to contribute to the pungent effects of eugenol.

At this point we have a clear picture of how eugenol may affectneuronal electrical activity. One important question that may berelevant in the context of this review is whether eugenol (or anyotherconstituent of essential oils) carries the potential for anti-convulsanteffects. A careful examination over the literature revealed only a few

studies pointing out the possible effects of eugenol in central nervoussystem (Dallmeier and Carlini, 1981; Wie et al., 1997; Masago et al.,2000; Irie et al., 2004). Throughout this review we showed thecomplex pharmacological profile of eugenol in blocking different ion

channels. Interesting to note is the fact that other anticonvulsantsubstances seems to exert its effects via multiple mechanisms Araujoet al. (2003). From a functional viewpoint, the simultaneous action ofeugenol over distinct ion channels may prevent the ability of neuronalcells to trigger action potentials and therefore makes it very attractive

as an anticonvulsant agent.In a very elegant study,Mlleret al.(2006)made use of different but complementary biological assays to explorethe neurophysiologic properties of theactionof eugenol. In order to dothat the authors investigated eugenol effects on 1) epileptiform field

potentials elicited by removal of extracellular Mg2+, 2) spreadingdepression induced by focal KCl microinjections, 3) electrically evoked

field potentials, and 4) long term potentiation in rat neocortical andhippocampal tissues. From their analyses we can conclude that

eugenol can suppress epileptiform field potentials and spreadingdepression, probably through inhibition of synaptic plasticity (Mlleret al., 2006). These very promisingresults indicate that further studies

are needed to clarify in more detail the putative beneficial effect ofeugenol in the treatment of epileptic patients.

Another constituent of essential oils that has been studied in thelast 10 years is menthol. It was first described as a cooling compound

and it had a prominent role in the elucidation of the so called coldsensors (McKemy et al., 2002). Menthol is a primary activator of thecold and menthol-sensitive TRPM8 channels (McKemy et al., 2002).After its binding to TRPM8 channels expressed in sensory neurons

there is a large increase in intracellular Ca2+ level which indirectlyfacilitates glutamate release. This process is very important in themodulatory effects of peripheral nociception provoked by menthol.

Until recently there was no evidence for distinct roles of menthol inthe nervous system. Mounting evidence, however, points to the factthat menthol could have effects in the central nervous system. Umezuet al. (2001) have shown that menthol when administered intrave-nously elicited profound effects on rodent behavior. The authors

reasoned that menthol caused its effects by acting on the centralnervous system. One would probably ask the question: How mentholreaches central nervous system? Menthol is absorbed and then bycrossing the blood-brain barrier (due to its lipophilic nature)

produces its effects on the neurons. Zhang et al. (2008) exploredthe effect of menthol in central neurons and they clearly demon-strated the central actions of menthol on hippocampal neurons. Moreinterestingly, they showed a specific function of menthol in arresting

the excitation of hippocampal neuronal cells by selectively augment-

ingtonic GABA inhibition. Thesefindingsare very relevant for thefield

542 D.A.M. de Arajo et al. / Life Sciences 89 (2011) 540544


4/5

because menthol could be used as an antiepileptic drug. In the samestudy, Zhang and colleagues used two different strategies to elicitepileptic activity and they provided compelling evidence thatmenthol does exert anticonvulsant effect and it is totally consistent

with the enhanced tonic GABAergic inhibition which preventsepileptiform neuronal hyperexcitability.

Watt et al. (2008) using Xenopus oocyte heterologous expression

system decided to investigate a possible modulation of recombinant

human GABAA receptors by menthol. This study was carried out todetermine whether menthol shares or not sites of action with othermost common sedative and anesthetic drugs. Firstly, they tested a

number of menthol analogs looking for an enhancement of GABAcurrents. Secondly, they described structurefunction relationshipscentered on receptor modulation. Thirdly, they finally exploredwhether menthol can act as a general anesthetic using an establishedbiological assay. The authors then concluded that menthol and its

chemical analogs share general anesthetic action with propofol (awell known anesthetic), probably through similar binding sites on theGABAA receptor.

It has been well known the antibacterial and antimycotic activity

of thymol (Botelho et al., 2007; Bakkali et al., 2008). However, someauthors have unequivocally demonstrated that this monoterpeneshowed effects on voltage-gated ion channels. One of such studiesperformed in isolated canine and human ventricular cardiomyocytes

demonstrated that thymol acted on cardiac ion channels in aconcentration-dependent manner provoking inhibitory effects on L-type Ca2+ currents and on various types of K+ currents such as,transient outward and delayed rectifier (Magyar et al., 2002). The

authors point to the fact that the mechanism of action may bedifferent when thymol blocks L-type Ca2+ channels and K+ channels.In a follow up study Magyar et al. (2004) investigated in more detailthe effects of terpenoid phenol derivatives (such as carvacrol, thymolandeugenol) on L-type Ca2+ current in isolated cardiac myocytes. The

authors then concluded that the blocking effect on cardiac Ca2+

currents may be related to the chemical nature of the substituent inthe benzene ring. In a very interesting study Haeseler et al. (2002)compared thymol andmenthol in their capacity to evoke a blockade in

voltage-gated Na+ currents. They discovered that both, thymol andmenthol inhibited voltage-gated neuronal and skeletal muscle Na+

channels in resting and inactivated states which strongly indicates a

voltage-dependent blockade which shares great similarity to the localanesthetic lidocaine.

Excitationcontraction coupling is a very important physiologicalprocess that maintain under control muscle contraction. It has been

reported that thymol had major effects on excitationcontractioncoupling in skeletal muscle of rodents (Szentesi et al., 2004).In a seriesof well designed experiments Szentesi et al.(2004) demonstrated thatthymol increases sarcoplasmatic reticulum (SR) Ca2+ release by acting

directly on the intracellular ryanodine receptor Ca2+ channel. Thymolalso hadeffects on intracellular Ca2+ handling incanine andguinea pigcardiac preparations (Szentandrassy et al., 2004). In a more recent

study it was reported that thymol increased intracellular Ca2+

concentration in pituitary GH3 cells (Shen et al., 2009). The authorsprovided evidence to state that thymol depletion of intracellular Ca2+

stores is related to thapsigargin-sensitive and -insensitive reservoirs.

Pitfalls and promises in the field

While many important findings related to natural products have

already been uncovered, we are still far from a through comprehen-sion of this very important topic of research. Many questions andchallenges remain to be solved. The main bottleneck for properlyexploring the molecular diversity of plant derived natural products is

an efficient purification platform that allows isolation in enoughquantities that can be screened against ion channels to look for new

pharmacological profiles.

Another important point to be discussed is related to thelimitations in identifying new compounds with highly desirablebiological activity. This limitation is worsened by seasonal orenvironmental variations that would certainly have a direct impact

in the biochemical composition of living organisms causing realproblems in the earlier purification steps. Finally, we would like tomake a reminder as to what was pointed out by Vries and colleaguesin a recent review it is obviousthat naturally occurring substances

especially those derived from higher plants, will continue to beessential tools in the discovery of therapeutic targets necessary for thedevelopment of new innovative drugs.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This work has been supported by research grants to Dr. D.A.M.

Arajo and Dr. J.S. Cruz (CNPq and FAPEMIG). Christiane Freitas heldan undergraduate scholarship from CNPq-RENORBIO.

ReferencesAkopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium

channel expressed by sensory neurons. Nature 1996;379:25762.Araujo DA, Mafra RA, Rodrigues AL, Miguel-Silva V, Beirao PS, de Almeida RN, et al.

N-salicyloyltryptamine, a new anticonvulsant drug, acts on voltage-dependentNa+, Ca 2+, and K+ ion channels. Br J Pharmacol 2003;140:13319.

Alves AMH, Gonalves JRC, Cruz JS, Arajo DAM. Evaluation of the sesquiterpene()--bisabolol as a novel peripheral nervous blocker. Neurosci Lett 2010;472:115.

Bakkali F, Averbeck S, Averbeck D, Idaomar M. Biological effects of essential oilsareview. Food Chem Toxicol 2008;46:44675.

Bickers D, Calow P, Greim H, Hanifin JM, Rogers AE, Saurat JH, et al. A toxicologic anddermatologic assessment of linalool and related esters when used as fragranceingredients. Food Chem Toxicol 2003;41:91942.

Bleakman D, Brorson JR, Miller RJ. The effect of capsaicin on voltage-gated calciumcurrents and calcium signals in cultured dorsal root ganglion cells. Br J Pharmacol1990;101:42331.

Botelho MA, Nogueira NA, Bastos GM, Fonseca SG, Lemos TL, Matos FJ, et al.

Antimicrobial activity of the essential oil from Lippia sidoides, carvacrol and thymolagainst oral pathogens. Braz J Med Biol Res 2007;40:34956.

Buchbauer G, Jirovetz L, Jager W, Dietrich H, Plank C. Aromatherapy: evidence forsedative effects of the essential oil of lavender after inhalation. Z Naturforsch C1991;46:106772.

Bulaj G. Integrating the discovery pipeline for novel compounds targeting ionchannels.Curr Opin Chem Biol 2008;12:4417.

Calixto JB, Kassuya CA, Andre E, Ferreira J. Contribution of natural products to thediscovery of the transient receptor potential (TRP) channels family and theirfunctions. Pharmacol Ther 2005;106:179208.

Catterall WA. Ion channel voltage sensors: structure, function, and pathophysiology.Neuron 2010;67:91528.

Celik S, Ozkaya A. Effects of intraperitoneally administered lipoic acid, vitamin E, andlinalool on the level of total lipid and fatty acids in guinea pig brain with oxidativestress induced by H2O2. J Biochem Mol Biol 2002;35:54752.

Cho JS, Kim TH, Lim JM, Song JH. Effects of eugenol on Na + currents in rat dorsal rootganglionneurons. BrainRes 2008;1243:5362.ChungG, Rhee JN,JungSJ, KimJS,OhSB. Modulation of CaV2.3 calcium channel currents by eugenol. J Dent Res 2008;87:13741.

Chung G, Rhee JN, Jung SJ, Kim JS, Oh SB. Modulation of Cav2.3 Calcium ChannelCurrents by Eugenol. J Dent Res 2008;87:13741.

Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception:implications for mechanisms of pain. Pain 2007;131:24357.

Dallmeier K, Carlini EA. Anesthetic, hypothermic, myorelaxant and anticonvulsanteffects of synthetic eugenol derivatives and natural analogues. Pharmacology1981;22:11327.

de Almeida RN, de Sousa DP, Nbrega FF, Claudino FS, Arajo DAM, Leite JR, et al.Anticonvulsant effect of a natural compound , -epoxy-carvone and its action onthe nerve excitability. Neurosci Lett 2008;443:515.

de Almeida RN, Araujo DAM, Goncalves JRC, Montenegro FC, de Sousa DP, Leite JR, et al.Rosewood oil induces sedationand inhibits compoundaction potential in rodents.JEthnopharmacol 2009;124:4403.

de Sousa DP, Goncalves JC, Quintans-Junior L, Cruz JS, Araujo DAM, de Almeida RN.Study of anticonvulsant effect of citronellol, a monoterpene alcohol, in rodents.Neurosci Lett 2006;401:2315.

Dib-HajjSD, BlackJA, Cummins TR,KenneyAM, Kocsis JD,WaxmanSG. Rescueof alpha-SNS sodium channel expression in small dorsal root ganglion neurons after

axotomy by nerve growth factor in vivo. J Neurophysiol 1998;79:266876.

543D.A.M. de Arajo et al. / Life Sciences 89 (2011) 540544


5/5

Dunlop J, Bowlby M, Peri R, Vasilyev D, Arias R. High-throughput electrophysiology: anemergingparadigmfor ion-channel screeningand physiology.Nature2008;7:35868.

Elisabetsky E, Marschner J, Souza DO. Effects of linalool on glutamatergic system in therat cerebral cortex. Neurochem Res 1995;20:4615.

Gonalves JC, Oliveira FS, Benedito RB, de Sousa DP, de Almeida RN, Arajo DAM.Antinociceptive activity of ()-carvone: evidence of association with decreasedperipheral nerve excitability. Biol Pharm Bull 2008;31:101720.

Goncalves JC, Alves AM, de Araujo AE, Cruz JS, Araujo DA. Distinct effects of carvoneanalogues on the isolated nerve of rats. Eur J Pharmacol 2010;645:108 12.

Haesele G, Maue D, Grosskreutz J, Bufler J, Nentwig B, Piepenbrock S, et al. Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and

menthol. Eur J Anaesthesiol 2002;19:5719.Hashimoto S, Uchiyama K, Maeda M, Ishitsuka K, Furumoto K, Nakamura Y. In vivo andin vitro effects of zinc oxide-eugenol (ZOE) on biosynthesis of cyclo-oxygenaseproducts in rat dental pulp. J Dent Res 1988;67:10926.

Hille B. Ionic Channels of Excitable Membranes. 3rd ed. Sunderland: Sinauer AssociatesInc; 2001. p. 50336.

Irie Y, Itokazu N, Anjiki N, Ishige A, Watanabe K, Keung WM. Eugenol exhibitsantidepressant-like activity in mice and induces expression of metallothionein-IIIin the hippocampus. Brain Res 2004;1011:2436.

Jirovetz L, Jager W, Buchbauer G, Nikiforov A, Raverdino V. Investigations of animalblood samples after fragrance drug inhalation by gas chromatography/massspectrometry with chemical ionization and selected ion monitoring. Biol MassSpectrom 1991;20:8013.

Kawai F. Odorant suppression of delayed rectifier potassium current in newt olfactoryreceptor cells. Neurosci Lett 1999;269:458.

Kawai F, Kurahashi T, Kaneko A. Nonselective suppression of voltage-gated currents byodorants in the newt olfactory receptor cells. J Gen Physiol 1997;109:26572.

Kawai F, Miyachi E. Odorants suppress voltage-gated currents in retinal horizontal cellsin goldfish. Neurosci Lett 2000;281:1514.

Leal-Cardoso JH, Silva-Alves KS, Ferreira-da-Silva FW, dos Santos-Nascimento T, JocaHC, de Macedo FH, et al. Linalool blocks excitability in peripheral nerves andvoltage-dependent Na+ current in dissociated dorsal root ganglia neurons. Eur JPharmacol 2010;645:8693.

Lee MH, Yeon KY, Park CK, Li HY, Fang Z, Kim MS, et al. Eugenol inhibits calciumcurrents in dental afferent neurons. J Dent Res 2005;84:84851.

Li HY, Park CK, Jung SJ, Choi SY, Lee SJ, Park K, et al. Eugenol inhibits K + currents intrigeminal ganglion neurons. J Dent Res 2007;86:898902.

Magyar J, Szentandrassy N, Banyasz T, Fulop L, Varro A, Nanasi PP. Effects of thymol oncalcium and potassium currents in canine and human ventricular cardiomyocytes.Br J Pharmacol 2002;136:3308.

Magyar J, Szentandrassy N, Banyasz T, Fulop L, Varro A, Nanasi PP. Effects of terpenoidphenol derivatives on calcium current in canine and human ventricularcardiomyocytes. Eur J Pharmacol 2004;487:2936.

Masago R, Matsuda T, Kikuchi Y, Miyazaki Y, Iwanaga K, Harada H, et al. Effects ofinhalation of essential oils on EEG activity and sensory evaluation. J PhysiolAnthropol Appl Human Sci 2000;19:3542.

McGivern JG, McDonough SI. Voltage-gated calcium channels as targets for thetreatment of chronic pain. Curr Drug Targets CNS Neurol Disord 2004;3:45778.

McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals ageneral role for TRP channels in thermosensation. Nature 2002;416:528.

Moreira-Lobo DC, Linhares-Siqueira ED, Cruz GM, Cruz JS, Carvalho-de-Souza JL, LahlouS, et al. Eugenol modifies the excitability of rat sciatic nerve and superior cervicalganglion neurons. Neurosci Lett 2010;472:2204.

Mller M, Pape HC, Speckmann EJ, Gorji A. Effect of eugenol on spreading depressionand epileptiform discharges in rat neocortical and hippocampal tissues. Neurosci-ence 2006;140:74351.

Narusuye K, Kawai F, Matsuzaki K, Miyachi E. Linalool suppresses voltage-gatedcurrents in sensory neurons and cerebellar Purkinje cells. J Neural Transm2005;112:193203.

Ohkubo T, Kitamura K. Eugenol activates Ca(2+)-permeable currents in rat dorsal rootganglion cells. J Dent Res 1997;76:173744.

Park CK, Kim K, Jung SJ, Kim MJ, Ahn DK, Hong SD, et al. Molecular mechanism for localanesthetic action of eugenol in the rat trigeminal system. Pain 2009;144:8494.

Park CK, Li HY, Yeon KY, Jung SJ, Choi SY, Lee SJ, et al. Eugenol inhibits sodium currents

in dental afferent neurons. J Dent Res 2006;85:9004.Peana AT, D'Aquila PS, Panin F, Serra G, Pippia P, Moretti MD. Anti-inflammatoryactivity of linalool and linalyl acetate constituents of essential oils. Phytomedicine2002;9:7216.

Perret D, Luo ZD. Targeting voltage-gated calcium channels for neuropathic painmanagement. Neurotherapeutics 2009;6:67992.

Petersen M, Wagner G, Pierau FK. Modulation of calcium-currents by capsaicin in asubpopulation of sensory neurones of guinea pig. Naunyn Schmiedebergs ArchPharmacol 1989;339:18491.

PizzoG, Giammanco GM,Cumbo E,NicolosiG, Gallina G. In vitroantibacterial activityofendodontic sealers. J Dent 2006;34:3540.

Shen AY, Huang MH, Wang TS, Wu HM, Kang YF, Chen CL. Thymol-evoked Ca+

mobilization and ion currents in pituitary GH3 cells. Nat Prod Commun 2009;4:74952.

Sugawara Y, Hara C, Aoki T, Sugimoto N, Masujima T. Odor distinctiveness betweenenantiomers of linalool: difference in perception and responses elicited by sensorytest and forehead surface potential wave measurement. Chem Senses 2000;25:7784.

Szentandrassy N, Szigeti G, Szegedi C, Sarkozi S, Magyar J, Banyasz T, et al. Effect of

thymol on calcium handling in mammalian ventricular myocardium. Life Sci2004;74:90921.

Szentesi P, Szappanos H, Szegedi C, Gonczi M, Jona I, Cseri J, et al. Altered elementarycalcium release events and enhanced calcium release by thymol in rat skeletalmuscle. Biophys J 2004;86:143653.

Umezu T, Sakata A, Ito H. Ambulation-promoting effect of peppermint oil andidentification of its active constituents. Pharmacol Biochem Behav 2001;69:38390.

Vriens J, Nilius B, Vennekens R. Herbal compounds andtoxins modulating TRPchannels.Curr Neuropharmacol 2008;6:7996.

Watt EE, Betts BA, Kotey FO, Humbert DJ, Griffith TN, Kelly EW, et al. Menthol sharesgeneral anesthetic activity and sites of action on the GABA(A) receptor with theintravenous agent, propofol. Eur J Pharmacol 2008;590:1206.

WieMB,Won MH,LeeKH, ShinJH, Lee JC,SuhHW, etal. Eugenolprotectsneuronal cellsfrom excitotoxic and oxidative injury in primary cortical cultures. Neurosci Lett1997;225:936.

Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic targets.Nat Rev Drug Discov 2009;8:982-1001.

Zamponi GW, Lewis RJ, Todorovic SM, Arneric SP, Snutch TP. Role of voltage-gatedcalcium channels in ascending pain pathways. Brain Res Rev 2009;60:849.

Zhang XB, Jiang P, Gong N, Hu XL, Fei D, Xiong ZQ, et al. A-type GABA receptor as acentral target of TRPM8 agonist menthol. PLoS One 2008;3:e3386.

544 D.A.M. de Arajo et al. / Life Sciences 89 (2011) 540544

Documents

Essential Oils Components as a New Path to Understand Ion Channel