molecules

Review Essential Oils and Their Constituents: An Alternative Source for Novel Antidepressants

Damião P. de Sousa 1 ID , Rayanne H. N. Silva 1, Epifanio F. da Silva 2 and Elaine C. Gavioli 2,*

1 Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, João Pessoa, PB 58051-970, Brazil; [email protected] (D.P.d.S.); [email protected] (R.H.N.S.) 2 Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN 59078-970, Brazil; [email protected] * Correspondence: [email protected]; Tel.: +55-84-3215-3419

Received: 6 July 2017; Accepted: 31 July 2017; Published: 3 August 2017

Abstract: Depression is a disease that has affected a high proportion of the world’s population and people of different ages, incapacitating them from good performance at work and in social relationships, and causing emotional disorders to millions of families. Therefore, the search for new therapeutic agents is considered a priority for the discovery of more effective forms of treatment. In this review, studies of essential oils and their constituents in experimental models related to depression are discussed. The mechanisms of action of the oils and the presence of psychoactive constituents in their chemical compositions are discussed. The data in the review show the therapeutic potential of essential oils and their chemical constituents for use in depressive disorders. Advanced studies using humans are needed to confirm the antidepressant properties described in animals.

Keywords: oil; terpene; natural products; major depression; antidepressant; animal models

1. Introduction Depression is one of the most prevalent and costly psychiatric disorders; it leads to substantial cognitive and affective disturbances, and negatively impacts the overall quality of life. Major depression is manifested through psychological, behavioral and physiological symptoms, comprised of depressed mood, markedly diminished pleasure in most activities, loss of energy, poor concentration, alterations in appetite and sleeping patterns, feelings of worthlessness, excessive guilt, and thoughts of death or suicide [1]. A systematic review has predicted an average prevalence for major depression at a global level of 4.7% [2]. This means that one out of every 20 people in the world is affected by depression. The prevalence estimated for depression in women was 5.9% and 3.8% for men [2]. Women are thus almost twice as likely to suffer from major depression as men.

2. Pharmacological Management of Major Depression Conventional antidepressant drugs ultimately act by increasing monoamine levels at the synaptic cleft by either: (i) blocking presynaptic monoamine transporter proteins, which remove released transmitters from the extracellular space; (ii) inhibiting the enzyme monoamine oxidase, which degrades monoamine neurotransmitters; or (iii) interacting with pre- or postsynaptic receptors that regulate monoamine transmitter release and/or neuronal firing rate [3]. It has been proposed that as antidepressant drugs increase extracellular monoamine concentrations, depression might be produced by deficiencies in noradrenaline, 5-HT and dopamine at their receptor sites in the brain. This proposal is known as the monoamine depression hypothesis [4]. Although the effects of antidepressants on monoamines can be seen soon after administration, it generally takes a few weeks of continued treatment for therapeutic responses to appear. Due to the therapeutic delay of

Molecules 2017, 22, 1290; doi:10.3390/molecules22081290 www.mdpi.com/journal/molecules Molecules 2017, 22, 1290 2 of 21 antidepressants, problems involving the neural network’s processing of information, rather than chemical disequilibrium, might well underlie depression [4]. In fact, conventional antidepressants mediate their effects by increasing Brain-Derived Neurotropic Factor (BDNF) in the forebrain regions, particularly in the hippocampus, making BDNF an essential determinant of antidepressant efficacy. BDNF acts in the brain inducing neuroplasticity, which results in depressive symptom improvements [5], and it has already been shown that hippocampal neurogenesis is a requirement for the therapeutic effects of antidepressants [6]. Depression pharmacotherapy is costly, though widely prescribed by physicians. However, less than half of the patients treated obtain complete remission through therapy with single antidepressant drugs. Some patients exhibit partial or no remission and some patients display treatment intolerance responses. This emphasizes the need to identify novel classes of antidepressants [7]. The most frequent side effects of these drugs are due to rapid monoamine concentration increases at the receptor sites. These effects could be summarized as increased anxiety, gastrointestinal and sexual problems and decreased alertness. The challenge for such new antidepressants is to achieve fast antidepressant response, broader efficacy, and fewer adverse effects [7]. Being a rich source for bioactive molecules, medicinal plants provide hope for development of novel antidepressant drugs [8–10]. An alternative approach might come from aromatic plants. Although certain essential oils found in plants have been used as traditional medicines, little scientific evidence supports their use. Essential oils are complex mixtures of volatile compounds produced by aromatic plants [11]. Recent clinical studies show that essential oils, inhaled or orally administered, enter the blood stream and exert psychological effects, thus complementing pharmacodynamic mediation. For instance, inhalation, or oral administration of essential oils improves the quality of sleep [12,13], attenuates symptoms of dementia [14,15], negative affect [16], anxiety [11,17], nicotine craving [18], post-traumatic stress disorder [19] and Alzheimer’s disease [20]. Preclinical pharmacological studies of essential oils and/or their isolated chemical constituents are becoming more common [21–24]. In fact, several studies have shown that the aromatherapy could to be used as a complementary and alternative therapy for patients with depression and secondary depressive symptoms [25], including anxiety disorders [26]. In a review published on plants used in aromatherapy for anxiety treatment, the contributions of the chemical constituents of their essential oils in this therapeutic effect are discussed [27], while a recent systematic review discusses the anxiolytic action of essential oils and their constituents [11]. The objective for this review is to discuss certain essential oils and their isolated constituents being tested in humans and rodents for treatment of major depression. These essential oils and their constituents have been pre-clinically tested for their antidepressant activity and are, respectively, illustrated in Tables1 and2. In addition, the proposed mechanisms by which essential oils and their isolated compounds produce antidepressant actions are also discussed. Considering all of the information herewith presented, essential oils might well be an alternative source of therapy for the relief of major depression symptoms.

3. Methodology The present study was carried out based on the literature review of plants and their essential oils with antidepressant activity. Chemical structure and name of bioactive compounds, as well as references are also provided. All species mentioned in the text were validated taxonomically on Database (www.theplantlist.orgW3Tropicos). The plant species presented here were selected based on the effects shown by their essential oils in specific animal models used for evaluation of antidepressant activity and/or by complementary studies, aimed at elucidating the mechanism(s) of action of the oils or individual components. To select the essential oil constituents, terms related to the theme, such as “essential oils”, “monoterpenes” and “phenylpropanoids”, were used, as well as names of representative compounds of these chemical groups refining with “antidepressant” or “depression”. A search was performed in the scientific literature database PubMed from 1995 to December 2015. The essential oils or the main constituents Molecules 2017, 22, 1290 3 of 21 were deemed to display antidepressant activity when they had shown effects in one or more different depressant model. The scientific publications were selected from studies published in English language.

4. Clinical Effects of Essential Oils on Mood Depression Certain clinical studies have been aimed at investigating the effects of essential oils in humans on mood and major depression. The most frequently studied essential oil for mood states is lavender, possibly due to its previously well-recognized anxiolytic effects [17]. Lavender oil capsules produced from Lavandula angustifolia Mill. (Lamiaceae) flowers were tested as an adjuvant therapy for major depression in patients under conventional pharmacological treatment [28]. In this pilot study, eight patients diagnosed with major depression and symptoms of anxiety, insomnia, and psychomotor agitation were treated with lavender oil for three weeks. The results demonstrated that lavender oil reduced certain anxiety related symptoms, psychomotor agitation, and sleep disturbances in the depressed patients, thus indicating significant improvements as compared to classical antidepressant medication alone [28]. The acute inhalation effects of lavender essential oil were investigated on moods in adult healthy men [29]. Electroencephalogragy (EEG) activity, alertness, and mood were assessed in 40 healthy adult men given 3 min (daily) of lavender oil inhalation. The subjects showed increased EEG beta power, reported feeling more relaxed, and with less depressive moods (as scaled by Profile of Mood States (POMS)); they also performed math computations faster and more accurately [29]. These findings suggest that lavender oil can improve moods even in healthy individuals. In another clinical pilot trial, the effects of an essential oil blend of Lavandula angustifolia Mill. and Rose otto (syn. Rosa × damascena Mill.), Rosaceae, in 28 postpartum women diagnosed with mild to moderate depression or anxiety [30]. The essential oil was administered by inhalation or using the dermal route (in a white lotion). Treatment consisted of 15 min sessions, twice a week for four consecutive weeks. The essential oils significantly relieved both depression symptoms (as scored by Edinburgh Postnatal Depression Scale (EPDS)), and anxiety (as scored by Generalized Anxiety Disorder Scale (GAD-7)). There were no adverse effects reported [30]. The study supported the beneficial effects of essential oils, in this case a combination of rose and lavender oils, for relief of depression and anxiety in postpartum women. Ultimately, this clinical study proposed an interesting approach combining distinct essential oils to better treat psychiatric disorders and/or comorbid diseases. Salvia sclarea L. (Lamiaceae) essential oil was tested in a pilot trial for modulation of depression signs in 22 women [31]. Normal and depressive tendencies and serum parameters in menopausal women acutely inhaling clary sage oil were assessed before and after exposition. Given the comparison between pre-inhalation and post-inhalation of clary sage oil, 5-HT plasma concentrations increased significantly, and plasma cortisol levels decreased significantly for both normal and depressive menopausal women [31]. It should be mentioned that this pioneering clinical trial contributed by measuring physiological changes alongside of behavioral alterations in women with depressive symptoms after acute clary sage oil inhalation. In a controlled, and randomized clinical pilot trial, the effect of continuous inhalation, in adult men with depression and under conventional pharmacological treatment, of citrus fragrance, (whose main component was lemon oil), was compared with that of no fragrance (n = 12 and 8, respectively) [32]. Four to eleven weeks of citrus fragrance inhalation significantly improved mood states, as scored by the Symptom Distress Scale (SDS) and the Hamilton Rating Scale for Depression (HRSD). The results indicated that therapeutic dosages necessary for treatment of depression can be markedly reduced. In fact, treatments with citrus oil normalized neuro-endocrine hormone levels and immune function [32]. This distinctly long-term clinical trial of citrus fragrance brings considerable insight to the beneficial effects of essential oils as therapy adjuvants for the treatment of major depression. Molecules 2017, 22, 1290 4 of 21

Table 1. Aromatic plant essential oils studied in experimental depression.

Administration via Dose Range Tested Essential Oils and Duration of Animal Specie and Minimal Active Behavioral Test Observed Effects Mechanism of Action Observations Reference Treatment Dose DR+ 30–240 mg/kg Reduced immobility time U-inverted curve Acorus tatarinowii Schott Oral gavage, acute ICR mouse FST, TST [33] (60 mg/kg) in both assays Controls: negative and positive (imipramine) Reversed the increase of CRF- and TH-positive cells in the paraventricular nucleus, and locus DR+ Asarum heterotropoides F. 0.25–2.0 g Reduced immobility time coeruleus, respectively; Controls: negative and Inhalation, acute ICR mouse FST, TST [34] Schmidt (0.25 g) in both tests positive (fluoxetine) Reversed the decrease of 5-HT-positive cells in the dorsal raphe nucleus

The treatment with flumazenil (GABAA antagonist), DR− buspirone (5-HT partial agonist), DOI (5-HT 1A 2A Controls: negative and receptor agonist), miaserin (5-HT receptor Saturated chamber 2A/C positive (fluoxetine and Citrus limon (L.) Osbeck Inhalation, acute ICR mouse FST Reduced immobility time agonist), apomorphin (D receptor agonist) and [35] (90 min) imipramine) haloperidol (D receptor antagonist) blocked the antidepressant effect. Increased hippocampal DA Reduced spontaneous and prefrontal cortex and hippocampal 5-HT locomotor activity DR− Controls: negative and Saturated chamber Citrus limon (L.) Osbeck Inhalation, acute SD rats FST Reduced immobility time positive (imipramine) [36] (60 min) Reduced spontaneous locomotor activity DR+ Controls: negative and positive (imipramine and 50–150 mg/kg paroxetine) Citrus limon (L.) Osbeck Oral gavage, 30 days Swiss mouse FST Reduced immobility time [37] (50 mg/kg) The treatment decreased spontaneous locomotion increased sleeping duration

The blockade of 5-HT2A/C, α1 and α2-receptors prevented the antidepressant effects; DR+ 1–50 mg/kg Eugenia uniflora L. Oral gavage, acute Swiss mouse TST Reduced immobility time In vitro inhibition of linoleic acid peroxidation; Controls: negative and [38] (10 mg/kg) positive (fluoxetine) Reduced SNP-induced lipoperoxidation in cortex, hippocampus and cerebellum DR+ Controls: negative and Lavandula angustifólia Mill. Intraperitoneal, acute SD rat 5–20% (5%) FST Reduced immobility time [39] positive (fluoxetine and imipramine) Molecules 2017, 22, 1290 5 of 21

Table 1. Cont.

Administration via Dose Range Tested Essential Oils and Duration of Animal Specie and Minimal Active Behavioral Test Observed Effects Mechanism of Action Observations Reference Treatment Dose DR− Saturated chamber Controls: negative and Lavandula angustifólia Mill. Inhalation, acute ICR mouse FST No effects were observed [35] (90 min) positive (fluoxetine and imipramine) DR+ Intraperitoneal, three 54.8–300 mg/kg Litsea glaucescens Kunth ICR mouse FST Reduced immobility time [40] times within 24 h (100 mg/kg) Controls: negative and positive (imipramine)

ICR mouse Saturated chamber DR− Mentha × piperita L. Inhalation, acute FST Reduced immobility time [41] (female) (10 min) Controls: negative Restored sucrose DR+ preference in CUMS mice; Reverted the reduced Reversed the 5-HT and 5-HIAA reduced 3–9 mg/kg CUMS, FST, TST, spontaneous locomotion in U-inverted curve Perilla frutescens L. Britton Oral gavage, 3 weeks ICR mouse concentrations in CUMS mice; [42] (3 mg/kg) OFT CUMS mice; Restored the serum IL-6, IL-1β, and TNF-α Restored increased levels in CUMS mice Controls: negative and immobility time in CUMS positive (fluoxetine) mice Restored the DR+ Oral gavage, 3 and 4 3–6 mg/kg CUMS, FST, CUMS-induced decreased Restored the CUMS-induced reduction of Perilla frutescens L. Britton ICR mouse [43] weeks (3 mg/kg) sucrose preference sucrose preference and hippocampal protein and mRNA BDNF Controls: negative and increased immobility time positive (fluoxetine) DR+ 0.1–100 mg/kg Rosmarinus officinalis L. Oral gavage, acute Swiss mouse TST Reduced immobility time [44,45] (0.1 mg/kg) Controls: negative and positive (fluoxetine) DR+

5–20% U-inverted curve Rosmarinus officinalis L. Intraperitoneal, acute SD rat FST Reduced immobility time [39] (5%) Controls: negative and positive (fluoxetine and imipramine)

The pretreatment with haloperidol (Dopamine DR+ 5–20% (5%); Intraperitoneal and Reduced immobility time receptor antagonist), SCH-23390 (D1 receptor Controls: negative and Salvia sclarea L. SD rat satured chamber FST [39] inhalation, acute when injected and inhaled antagonist) and buspirone (5-HT partial agonist) (1, 2, 4 and 6 h) 1A positive (fluoxetine and blocked the antidepressant effect imipramine) Restored increased DR− Schinus terebinthifolius immobility time in rats Oral gavage, 15 days Wistar rats 100 mg/kg FST [46] Raddi subjected to a model of Controls: negative and neuropathic pain positive (ketamine) DR+ Syzygium aromaticum (L.) 50–200 mg/kg Reduced immobility time Controls: negative and Oral gavage, acute ICR mouse FST, TST [47] Merr, & L.M.Perry (100 mg/kg) in both tests positive (imipramine) LD50 = 45564.556 g/kg (po) Molecules 2017, 22, 1290 6 of 21

Table 1. Cont.

Administration via Dose Range Tested Essential Oils and Duration of Animal Specie and Minimal Active Behavioral Test Observed Effects Mechanism of Action Observations Reference Treatment Dose Restored sucrose preference in CUMS rats; CUMS, DR+ Syzygium aromaticum (L.) 50–200 mg/kg Reverted the increased Restored hippocampal BDNF protein, p-ERK and Oral gavage, 5 weeks novelty-suppressed [47] SD rat latency to feed in a Merr, & L.M.Perry (50 mg/kg) feeding behavior p-CREB expression unfamiliar environment in Controls: negative and CUMS rats positive (imipramine) Thymus vulgaris L. ICR mouse Saturated chamber DR− Inhalation, acute FST Reduced immobility time [41] (Lamiaceae) (female) (10 min) Controls: negative Toona ciliata Roem. var. 10–80 mg/kg Reduced immobility time DR+ Oral gavage, acute ICR mouse FST, TST [48] yunnanensis (C. DC.) C.Y. (10 mg/kg) in both tests Controls: negative and WU positive (imipramine) Increased hippocampal monoamines (5-HT, NE and Toona ciliata Roem var. 10–80 mg/kg No behavioral effects were DR+ Oral gavage, acute SD rat CUMS DA) and BDNF contents in CUMS rats; [48] yunnanensis (C. DC.) C.Y. (10 mg/kg) evaluated Controls: negative and WU Reduced serum corticosterone in CUMS rats positive (imipramine) Increased noradrenaline and 5-HT levels after repeated administration; The acute antidepressant Albino Laca effect was prevented by pretreatment with L-arginine DR+ Oral gavage, acute 10–40 mg/kg [49] Valeriana wallichii mouse (male FST Reduced immobility time (NO precursor) and sildenafil (phosphodiesterase 5 DC. and 14 days (10 mg/kg) and female) inhibitor), while it was potentiated with L-NAME (NOS inhibitor) and methylene blue (inhibitor of Controls: negative and soluble guanylate cyclase) positive (imipramine) ICR mouse Saturated chamber DR− Zingiber officinale Roscoe Inhalation, acute FST Reduced immobility time [41] (female) (10 min) Controls: negative FST: forced swimming test; TST: tail suspension test; OFT: open field test; CUMS: Chronic unpredictable mild stress; DR−: absence of dose/concentration response; DR+: dose/concentration response design; 5-HT: serotonin; DA: dopamine; NE: noradrenaline. Molecules 2017, 22, 1290 7 of 21

5. Antidepressant-Like Effects of Essential Oils: Evidence from Animal Studies As summarized in Table1, the following essential oils of plants displayed some antidepressant-like effects when tested in rodents: essential oils of Acorus tatarinowii Schott (Acoraceae), Asarum heterotropoides F. Schmidt (Aristolochiaceae), Citrus limon (L.) Osbeck (Rutaceae), Eugenia uniflora L. (Myrtaceae), Lavandula angustifolia Mill, Litsea glaucescens Kunth (Lauraceae), Mentha × piperita L. (Lamiaceae), Perilla frutescens (L.) Britton (Lamiaceae), Rosmarinus officinalis L. (Lamiaceae), Salvia sclarea L., Schinus terebinthifolius Raddi (Anacardiaceae), Syzygium aromaticum (L.) Merr. & L.M. Perry (Myrtaceae), Toona ciliata Roem var. Yunnanensis (C. DC.) C.Y. Wu (Meliaceae), Valeriana wallichii DC. (Caprifoliaceae), and Zingiber officinale Roscoe (Zingiberaceae). The most promising aromatic plants with significant evidence of antidepressant-like effects and the putative mechanisms by which they act are detailed below. Indeed, the main constituents of some of these essential oils have been already isolated, identified, and even tested for antidepressant effects in rodents.

5.1. Asarum heterotropoides F. Schmidt (Aristolochiaceae) Recently, a study showed for the first time the antidepressant-like effects of Asarum heterotropoides F. Schmidt essential oil (from the roots) in mice [34]. The chemical composition of this essential oil was analyzed; 78 peaks were detected by gas chromatography. The main compounds are methyl eugenol (22%), pentadecane (6%), and 2,3,5-trimethoxytoluene (5%). Antidepressant-like effects were observed after acute inhalation in behavioral despair assays (e.g., forced swimming and tail suspension tests) in mouse. Considering the prevalence of methyl eugenol in the Asarum heterotropoides F. Schmidt essential oil, and the antidepressant-like actions previously reported about this compound in rats [50], it might be suggested the methyl eugenol as the main mediator of the antidepressant effects induced by Asarum heterotropoides F. Schmidt. Immunohistochemistry was performed to investigate the mechanisms of action. An increase in the CRF- and tyrosine hidroxylase-positive cells in the paraventricular nucleus and locus coeruleus, respectively, and a significant decrease of 5-HT-positive cells was observed in the mouse dorsal raphe after forced swimming exposure. The inhalation of Asarum heterotropoides F. Schmidt essential oil restored to normal levels the immunoreactivity to 5-HT, CRF and tyrosine hidroxylase. Considering that stress-induced depression-like behaviors are closely linked to increased activity of the endogenous peptidergic system of CRF and reduced availability of monoamines [51], the mechanistic findings herein reported could be on the basis of the antidepressant-like effects of Asarum heterotropoides F. Schmidt oil.

5.2. Citrus limon L. Osbeck Acute inhaled lemon oil reduced immobility time in the FST in rats and mice [35,36]. However, in the same studies, inhalation of this oil reduced locomotion and exploration in the open field, which would be suggestive of a sedative effect [35,37]. Later, Lopes et al. [37] evaluated prolonged oral effects of Citrus limon L. Osbeck oil (from the leaves) in mice in the FST. Antidepressant, anxiolytic and hypolocomotor effects in animal were reported in a dose-dependent manner. A mixture of monoterpenes was detected in the Citrus limon L. Osbeck essential oil, among which limonene (53%), geranyl acetate (10%) and trans-limonene-oxide (7%) were the main compounds [37]. Contrasting findings are available in literature regarding the effects of limonene on mood states in rodents. After acute administration, the monoterpene was inactive in the mouse FST [40]. However, under prolonged treatment (15 days), limonene reversed increased immobility time in the FST induced by neuropathic pain in rats [46]. The putative mechanism by which lemon oil produces antidepressant-like effects seems to be mediated by 5-HT and dopamine neurotransmission. The pretreatment with buspirone (5-HT1A partial agonist), DOI (5-HT2A receptor agonist), miaserin (5-HT2A/C receptor agonist), apomorphin (nonselective dopamine receptor agonist) and haloperidol (nonselective dopamine receptor antagonist), blocked the antidepressant effects of lemon oil [35]. Moreover, the acute Molecules 2017, 22, 1290 8 of 21 inhalation of this oil significantly increased dopamine contents in the hippocampus and 5-HT in the prefrontal cortex and hippocampus [35]. As commented before, dopamine and 5-HT are intrinsically involved in the modulation of mood states, and hippocampus and prefrontal cortex are the main stages of this action [4]. Thus, the antidepressant-like effects of Citrus limon L. Osbeck oil might be mediated by limonene. Indeed, modulation of 5-HT and dopamine neurotransmission in brain areas highly involved with mood states could be on the basis of the antidepressant effects of lemon oil.

5.3. Eugenia uniflora L. The potential antidepressant-like effects of Eugenia uniflora L. essential oil showed in a dose-dependent manner after acute administration in the TST in mice [38]. The chemical composition of Eugenia uniflora L. oil was analyzed by gas chromatography/mass spectroscopy; and it contains mainly sesquiterpenes: germacrene B (22%), selina-1,3,7-trien-8-one-oxide (19%), β-caryophyllene (13%), germacrene A (11%), germacrene D (11%), selina-1,3,7-trien-8-one (9%) and curzerene (4%). Only β-caryophyllene has been tested for the effects on depression states. The acute administration of β-caryophyllene induced robust antidepressant-like effects, as replicated in distinct animal models in mice: FST, TST, and novelty-suppressed feeding behavior [52]. Indeed, the antidepressant effects of the isolated constituent β-caryophyllene were prevented by the pretreatment with a CB2 receptor antagonist, AM630 [52]. Interestingly, β-caryophyllene acts as a CB2 receptor agonist [53]. The CB2 receptor is expressed also in the brain, and is involved in the modulation of anxiety and depressive states [54]. Victoria et al. [38] showed the involvement of monoamines neurotransmission mediating the Eugenia uniflora L. oil-induced antidepressant actions. The blockade of 5-HT2A/C, α1- and α2-receptors prevented the antidepressant effects of this essential oil in the mouse TST. Additional studies aimed to investigate the effects of chronic administration of Eugenia uniflora L. oil in animal models of depression and putative mechanisms of action are worth carrying out.

5.4. Perilla frutescens L. Britton Two distinct research groups from China have described the antidepressant effects of Perilla frutescens L. Britton essential oil in mice. Using the chronic unpredictable mild stress (CUMS), a well validated animal model of depression, these studies showed the effects of the essential oil in reversing behavioral, neurochemical, and immunological alterations induced by stress [42,43]. The essential oil restored sucrose-preference in stressed mice, a behavior intrinsically related to anedonia, a core symptom of depression. In addition, the treatment with this oil also restored the increased immobility time in the FST and TST in CUMS mice, thus supporting a robust antidepressant-like action [42,43]. Changes in 5-HT and BDNF levels might be based on the antidepressant actions. The administration of the essential oil effectively reversed the reduced hippocampal concentrations of 5-HT, its metabolite, 5-HIAA, and BDNF protein and mRNA [42,43]. A growing body of evidence supports the release of pro-inflammatory cytokines, mainly IL-1β, IL-6, and TNF-α, in major depression [55]. The chronic administration of Perilla frutescens L. Britton oil dose-dependently decreased the serum IL-6, IL-1β, and TNF-α levels in CUMS-mice. The main constituents of this essential oil extracted by supercritical fluid are L-perillaldehyde, limonene, beta-caryophyllene, selinene, santalene and bergamotene [56]. L-perillaldehyde-induced antidepressant-like effects have already been reported in mice [42,57]. Repeated administration (oral and inhalated) of this compound reversed depressant-like behaviors induced by CUMS and lipopolyssacaride (LPS) [42,57]. Concerning the mechanism of action of L-perillaldehyde on depressive states, restored concentrations of 5-HT and noradrenaline in the prefrontal cortex were observed in LPS-treated mice, and attenuated LPS-induced increases of TNF-α and IL-6 levels [42]. The Perilla frutescens L. Britton oil has other compounds with antidepressant-like actions, such as limonene and beta-caryophyllene [46,52]. Taken together, the robust antidepressant effects of Perilla frutescens L. Britton oil suggest that more than one active compound, with distinct mechanisms of action, could be mediating this effect. Molecules 2017, 22, 1290 9 of 21

5.5. Salvia sclarea L. The antidepressant effects of essential oil of Salvia sclarea L. were assessed in the FST in rats. The acute exposition to this oil, via intraperitoneal and inhalation, reduced immobility time similar to conventional antidepressant drugs [39]. The antidepressant effects of this essential oil seem to be mainly mediated by the activation of dopamine and 5-HT neurotransmission [39]. In fact, the pretreatment with haloperidol (Dopamine receptor antagonist), SCH-23390 (D1 receptor antagonist), but also buspirone (5-HT1A partial agonist) blocked the antidepressant effect of this essential oil [39]. The principal constituents of Salvia sclarea L. oil include linalyl acetate (64%), linalool (21%), and geraniol (2.6%) [32]. Linalool and geraniol have showed consistent antidepressant actions in rodents after acute administrations [40,58–60]. This effect of linalool in rodents were prevented with WAY100,635 (5-HT1A receptor antagonist) and yohimbine (α2-receptor antagonist), thus reinforcing the role mediated by monoaminergic neurotransmission in the antidepressant effects of linalool [58]. Ultimately, the antidepressant of the Salvia sclarea L. essential oil seems to be due to the synergic effects of bioactive isolated compounds.

5.6. Syzygium aromaticum (L.) Merr. & L.M. Perry Recently, a well-designed study showed the antidepressant effects of S. aromaticum essential oil in rodents. After acute administration, this essential oil reduced immobility time in mice in the FST and TST. Using the CUMS, chronic administration of S. aromaticum (L.) Merr. & L.M. Perry oil restored sucrose preference and reversed the increased latency to feed in an unfamiliar environment in CUMS rats [47]. The antidepressant doses (50–200 mg/kg) were, at least, 22-fold higher than the lethal dose 53 (LD50 = 4.5 g/kg). The chronic administration of this essential oil restored hippocampal BDNF, p-ERK and p-CREB protein expression in CUMS rats [47]. The major compounds identified in S. aromaticum (L.) Merr. & L.M. Perry essential oil were eugenol (71%), β-caryophyllene (10%), eugenyl acetate (16%) [47]. Literature findings support antidepressant-like actions for eugenol and β-caryophyllene [52,61,62], which could be synergically mediating the antidepressant effects of the S. aromaticum (L.) Merr. & L.M. Perry oil. Repeated administration of eugenol reduced immobility in the TST and FST [61,62]. The antidepressant effects of eugenol were attributed to the inhibition of human MAOA [60], and the increase in hippocampal BDNF [61]. These findings suggest that eugenol, but also β-caryophyllene could be mediating the antidepressant-like actions of S. aromaticum (L.) Merr. & L.M. Perry essential oil by the increase in monoamine neurotransmission and neuroplastic actions.

5.7. Toona ciliata var. yunnanensis (C. DC.) C.Y. Wu The acute administration of T. ciliata var. Yunnanensis (C. DC.) C.Y. Wu oil evoked antidepressant-like actions in a dose-dependent manner in mice, in the FST and TST [48]. In addition, the treatment with this essential oil increased hippocampal monoamines (5-HT, noradrenaline and dopamine) and BDNF contents in CUMS rats [48]. The major compounds identified in T. ciliata var. Yunnanensis (C. DC.) C.Y. Wu oil by gas chromatography/mass spectroscopy were β-elemene (25%), β-cubebene (14%), γ-elemene (8%), and estragole (6%) [48]. None of these components have been tested yet for the effects on depressive states. Further studies aimed to evaluate the effects of the isolated oil compounds and the T. ciliata var. Yunnanensis (C. DC.) C.Y. Wu oil during chronic administration in animal models of depression are warranted.

5.8. Valeriana wallichii DC. The effects of Valeriana wallichii DC. (patchouli alcohol chemotype) were tested in the mouse FST after acute and 14-days administration [49]. The acute treatment with this essential oil reduced, in a dose-dependent manner, the immobility time of mice in the FST; the antidepressant doses in this assay were 20 mg/kg and 40 mg/kg [49]. However, after repeated administration, the V. wallichii DC. oil reduced immobility time only at 20 mg/kg [49]. Chronic administration Molecules 2017, 22, 1290 10 of 21 increased norepinephrine and 5-HT levels in the mouse brain [61]. More evidence suggests the participation of nitric oxide signaling pathway in the acute antidepressant-like effect of V. wallichii DC. essential oil. The pretreatment with L-arginine (NO precursor) and sildenafil (phosphodiesterase 5 inhibitor) prevented the antidepressant effect, while it was potentiated with L-NAME (NOS inhibitor), and methylene blue (inhibitor of soluble guanylate cyclase) [49]. These findings are in accordance with previous studies that showed reduction of NO levels within the brain inducing antidepressant-like effects [63–65]. Classical antidepressant drugs induce behavioral effects in the FST via blockade of nitregic system pathway [66,67]. The V. wallichii DC. oil constituents were identified by gas chromatography-mass spectroscopy. The oil contains patchouli alcohol (40%) as the major constituent followed by the presence of δ-guaiene (10%), seychellene (8%), 8-acetoxyl patchouli alcohol (4%) and virdiflorol (5%). These isolated compounds have not still tested on experimental depression. Further studies, aimed at investigating the effects of these isolated compounds as well as the effects of V. wallichii DC. essential oil on depression in rodents, are needed [49]. Molecules 2017, 22, 1290 11 of 21

Molecules 2017, 22, 1290 11 of 22 Molecules 2017, 22, 1290 Table 2. Constituents from essential oils tested in experimental depression. 11 of 22 Molecules 2017, 22, 1290 11 of 22 Molecules 2017, 22, 1290 Table 2. Constituents from essential oils tested in experimental depression. 11 of 22 Via of Table 2. ConstituentsDose from Range essential oils tested in experimental depression. Via of Administration TableDose 2.Range Constituents Tested Tested from and essential oils tested in experimental depression. Constituents AdministrationVia of AnimalAnimal Specie Behavioral Test Observed Effects Mechanism of Action Observations Reference Constituents and Duration of TableDoseand Range2. Minimal Constituents Tested Minimal Behavioral from Active essential Test oils tested Observed in experimental Effects depression. Mechanism of Action Observations Reference andAdministration DurationVia of of AnimalSpecie Constituents Treatment DoseandActive Range Minimal Dose Tested DoseBehavioral Test Observed Effects Mechanism of Action Observations Reference andAdministrationTreatment DurationVia of of AnimalSpecie Constituents DoseandActive Range Minimal Dose Tested Behavioral Test Observed Effects Mechanism of Action Observations Reference andAdministrationTreatment Duration of AnimalSpecie Constituents andActive Minimal Dose Behavioral Test Observed Effects Mechanism of Action Observations Reference andTreatment Duration of Specie Active Dose OMe Treatment DR+ [33] DR+ [33] OMe Intraperitoneal, 5–20 mg/kg Reduced immobility time in Intraperitoneal,ICR mouse 5–20 mg/kgFST, TST (10 Reduced immobility time in both DR+ [33] MeO OMe Intraperitoneal,acute ICR mouse5–20(10 mg/kg) mg/kg ReducedFST,both immobility TST assays time in acute ICR mouse mg/kg)FST, TST assays DR+ [33] MeO OMe Intraperitoneal,acute 5–20(10 mg/kg) mg/kg Reducedboth immobility assays time in OMe ICR mouse FST, TST DR+ [33] MeO Intraperitoneal,acute (105–20 mg/kg) mg/kg Reducedboth immobility assays time in OMe ICR mouse FST, TST Controls: negative and Asarone acute (10 mg/kg) both assays Controls: negative and MeOAsaroneOMe Controls:positive (imipramine) negative and Asarone positive (imipramine) OMe Controls:positive (imipramine)negative and Asarone Reduced immobility time in Controls:positive (imipramine) negative and Asarone FST, TST, Reducedthe TST immobility and the FST; time in The pretreatment with AM630 positive (imipramine) Intraperitoneal, C57BL/6 novelty-suppressFST, TST, Reduced immobility time in the DR− [52] 50 mg/kg Reduceddecreasedthe TST immobility feeding and the latency FST; time in (CBThe2 pretreatmentantagonist) prevented with AM630 the Intraperitoneal,acute C57BL/6mouse novelty-suppressedFST, feeding TST, FST, TST, TST and the FST; decreased TheDR pretreatment− with[52]AM630 (CB2 DR− [52] Intraperitoneal, 50 mg/kg decreasedReducedthethe novelty-suppressed TST immobility feeding and the latency FST; time in The(CB 2anti-immobilitypretreatment antagonist) prevented with effects AM630 the Intraperitoneal,acute C57BL/6mouseC57BL/6 mouse 50novelty-suppress mg/kgedFST,behavior feeding TST, novelty-suppressed feeding latency in the DRantagonist)− prevented[52] the acute 50 mg/kg decreasedthethe novelty-suppressed TSTfeeding feeding and testthe latency FST; in (CBThe2anti-immobility pretreatmentantagonist) prevented with effects AM630 the β Intraperitoneal,acute C57BL/6mouse novelty-suppressedbehavior feeding feeding behavior novelty-suppressed feeding test DR− anti-immobility[52] effects -Caryophyllene 50 mg/kg decreasedthe novelty-suppressedfeeding feeding test latency in (CBanti-immobility2 antagonist) prevented effects the Controls: negative acute mouse edbehavior feeding β-Caryophyllene the novelty-suppressedfeeding test anti-immobility effects Controls: negative β-Caryophyllene behavior Controls: negative β -CaryophylleneOH feeding test Controls: negative β-CaryophylleneOH The pretreatment with Controls: negative OH SCH23390The pretreatment (D1 antagonist) with and DR+ [68] Oral gavage, Swiss 12.5–50 mg/kg Reduced immobility time in OH FST, TST SCH23390sulpirideThe pretreatment (D (D1 antagonist)2 antagonist) with and DR+ [68] Oralacute gavage, mouseSwiss 12.5–50(12.5 mg/kg) mg/kg Reduced bothimmobility tests time in The pretreatment with SCH23390 (D1 FST, TST SCH23390preventedsulpirideThe pretreatment (Dthe (D1 antagonist)anti-immobility2 antagonist) with and DR+ [68] DR+ [68] Oralacute gavage, mouseSwiss 12.5–50(12.5 mg/kg) mg/kg Reduced immobilityboth tests time in antagonist) and sulpiride (D2 antagonist) 12.5–50FST, mg/kg TST ReducedpreventedSCH23390sulpiride immobility the(D effects(D1 anti-immobility2antagonist) antagonist) time inand both DR+ [68] OralOralacute gavage, acutemouseSwiss Swiss mouse12.5–50(12.5 mg/kg) mg/kg ReducedFST, bothimmobility TST tests time in prevented the anti-immobility effects (12.5 mg/kg)FST, TST preventedsulpiride theeffects tests(D anti-immobility2 antagonist) Controls: negative and Carvacrol acute mouse (12.5 mg/kg) both tests prevented theeffects anti-immobility Controls:positive (imipramine) negative and Carvacrol OH effects Controls:positive (imipramine)negative and Carvacrol Controls: negative and OHCarvacrol Controls:positive (imipramine) negative and Carvacrol OH Reversed the increased positive (imipramine) positive (imipramine) hippocampalReversed COX-2 the increased protein and OH SD rat, 18 Reversed decreased sucrose Oral gavage, 21 22.5–90 mg/kg hippocampalactivity;Reversed Reversed COX-2 the increased the protein elevated and DR+ [69] SDmonths rat, 18 CUMS preferenceReversed decreased and spontaneous sucrose Oral gavage,days 21 22.5–90(45 mg/kg) mg/kg hippocampalactivity;PGEReversed2 concentration Reversed COX-2 the increased the protein in elevated frontal and DR+ [69] SDmonths oldrat, 18 CUMS Reversedpreferencelocomotion decreased and in spontaneousCUMS sucrose rats Oral gavage,days 21 22.5–90(45 mg/kg) mg/kg hippocampalactivity;PGEcortex2 concentration andReversed hippocampusCOX-2 the proteinin elevated frontal in and DR+ [69] SDmonths oldrat, 18 CUMS preferenceReversedlocomotion decreased and in spontaneous CUMS sucrose rats Reversed the increased hippocampal Oral daysgavage, 21 22.5–90(45 mg/kg) mg/kg Reversedactivity;PGEcortex2 concentration andReversedCUMS decreased hippocampus rats the in elevated frontal sucrose in DR+ [69] DR+ [69] monthsold CUMS preferencelocomotion and in CUMSspontaneous rats COX-2 protein and activity; Reversed the Oraldays gavage, 21 SD rat,(45 18 mg/kg) 22.5–90 mg/kg (45 preferencePGEcortex2 concentration andCUMSand hippocampus spontaneousrats in frontal in old locomotion in CUMS rats elevated PGE2 concentration in frontal Cinnamic aldehyde CUMS Controls: negative and days months old mg/kg) locomotioncortex andCUMS hippocampus in rats CUMS rats in cortex and hippocampus in CUMS rats Cinnamic aldehyde CUMS rats Controls: negative and Cinnamic aldehyde Controls: negative and Molecules 2017, 22, 1290 12 of 22 Cinnamic aldehyde Controls: negative and Controls: negative and Cinnamic aldehyde positive (fluoxetine) positive (fluoxetine) DR− [36]

O DR− [36] Saturated chamberSaturated chamber Controls: negative and Inhalation,Inhalation, acute acute SD rats SD rats FST ReducedFST immobility time Reduced immobility time (60 min) (60 min) positive (imipramine) Controls: negative and positive (imipramine) Citral Hypolocomotion Citral Hypolocomotion O O (CH2)5CH3 DR+ [45][70] Intraperitoneal, Wistar rat 0.1–0.3 g/kg FST No effects acute Controls: negative γ-Decanolactone Hypolocomotion at higher doses

O Intraperitoneal, DR− [40] three times ICR mouse 100 mg/kg FST No effects within 24 h

Controls: negative and Eucalyptol positive (imipramine) DR+ [61] Increased Hippocampal BDNF Reduced immobility time in and metallothionein-III Intraperitoneal, 10–100 mg/kg the TST and increased ddY mice FST, TST (brain-predominant protein that Controls: negative and 14 days (30 mg/kg) number of wheel rotations alleviates various neurotoxic positive (imipramine) in the FST MeO events) mRNA OH

Oral, mixed with Inhibits human MAOA (IC50 34.4 DR− [62] Increased number of wheel Eugenol drinking water, ICR mouse 0.17 mmol/kg FST µM) preferencially than MAOB rotations in the FST Controls: negative 14 days (IC50 288 µM) activity

Reversed the IL-1β-related CNS OH Restored decreased sucrose inflammation by markedly preference and increased inhibiting CUMS-induced PFC DR+ [60] Oral gavage, 4 20–40 mg/kg ICR mouse CUMS, FST, TST immobility time in the TST NF-κB pathway and modulating weeks (20 mg/kg) and FST in mice subjected NLRP3 inflammasome activation to CUMS (activated caspase 1) in CUMS Controls: negative and Geraniol mice positive (fluoxetine)

Molecules 2017, 22, 1290 12 of 21 Molecules 2017, 22, 1290 12 of 22 Molecules 2017, 22, 1290 12 of 22 Molecules 2017, 22, 1290 12 of 22 positive (fluoxetine) Table 2. Cont. positiveDR (fluoxetine)− [36] positive (fluoxetine) DR− [36] DR− [36] O O Via of Dose Range Saturated chamber Controls: negative and O Inhalation,Administration acute SD rats Tested andFST Reduced immobility time Constituents AnimalSaturated Specie(60 min) chamber Behavioral Test Observed EffectsControls:positive (imipramine) negative Mechanism and of Action Observations Reference Inhalation,and Duration acute of SD rats Saturated chamberMinimal ActiveFST Reduced immobility time Controls: negative and Inhalation, acute SD rats (60 min) FST Reduced immobility time positive (imipramine) Treatment (60 min) Dose positive (imipramine)

O O Citral Hypolocomotion O Citral(C H2)5CH3 Hypolocomotion DR+ [45,70] OCitral Hypolocomotion O O (CH2)5CH3 DR+ [45][70] O O Intraperitoneal, (CH2)5CH3 Intraperitoneal, Wistar rat 0.1–0.3 g/kg FST No effects DR+ [45][70] (CH2)5CH3 acute Wistar rat 0.1–0.3 g/kg FST No effects DR+ [45][70] Controls: negative Intraperitoneal,acute Controls: negative γ-Decanolactone Intraperitoneal, Wistar rat 0.1–0.3 g/kg FST No effects Hypolocomotion at γ-Decanolactone acute Wistar rat 0.1–0.3 g/kg FST No effects HypolocomotionControls: negative at acute Controls: negative γ-Decanolactone Hypolocomotionhigher doses at higher doses γ-Decanolactone Hypolocomotion at higher doses higher doses

O Intraperitoneal, DR− [40] DR− [40] Intraperitoneal,threeIntraperitoneal, times ICR mouse 100 mg/kg FST No effects DR− [40] O Intraperitoneal, 100 mg/kg DR− [40] O threewithinthree timestimes 24 h withinICR mouseICR mouse 100 mg/kg FST NoFST effects No effects three times ICR mouse 100 mg/kg FST No effects within 24 h h within 24 h Controls: negative and Eucalyptol Controls: negative and Eucalyptol Controls:positive (imipramine) negative and Eucalyptol Controls: negative and positive (imipramine) Eucalyptol positive (imipramine)DR+ [61] positive (imipramine) Increased Hippocampal BDNF DR+ [61] Reduced immobility time in DR+ [61] Increasedand metallothionein-III Hippocampal BDNF Intraperitoneal, 10–100 mg/kg Reducedthe TST immobility and increased time in ReducedIncreased immobility Hippocampal time BDNF in the Increased Hippocampal BDNF and DR+ [61] ddY mice FST, TST Reduced immobility time in (brain-predominantand metallothionein-III protein that Controls: negative and Intraperitoneal,Intraperitoneal,14 days 10–100(30 mg/kg) mg/kg 10–100 mg/kg numberthe TST of andwheel increased rotations TST andand metallothionein-III increased number of metallothionein-III (brain-predominant Intraperitoneal, ddY mice ddY mice10–100 mg/kg FST, TST the FST,TST and TST increased (brain-predominantalleviates various neurotoxic protein that Controls:positive (imipramine) negative and 14 days14 days ddY mice (30 mg/kg) (30 mg/kg)FST, TST number inof thewheel FST rotations (brain-predominantwheel rotations inprotein the FST that Controls:protein negative that alleviates and various neurotoxic MeO 14 days (30 mg/kg) number of wheel rotations alleviatesevents) various mRNA neurotoxic positive (imipramine) in the FST alleviates various neurotoxic positive (imipramine) MeO OH in the FST events) mRNA events) mRNA Controls: negative and MeO OH events) mRNA positive (imipramine) Oral, mixed with Inhibits human MAOA (IC50 34.4 DR− [62] OH Increased number of wheel Eugenol Oral,drinkingOral, mixed mixed water, with withICR mouse 0.17 mmol/kg FST InhibitsµM) preferencially human MAO thanA (IC50 MAO 34.4B InhibitsDR− human MAO[62]A (IC50 34.4 µM) − Oral, mixed with Increasedrotations number in the of FST wheel InhibitsIncreased human number MAOA of(IC50 wheel 34.4 Controls:DR negative− [62] DR [62] Eugenol drinking water, ICR mouse 0.17 mmol/kg FST µM) preferencially50 than MAOB Eugenol drinking14 days water, ICR mouse 0.17 mmol/kg IncreasedFST number of wheel (IC 288 µM) activity preferencially than MAOB (IC50 288 µM) Eugenol drinking water, ICR mouse 0.17 mmol/kg FST rotations in the FST µM)rotations preferencially in the than FST MAOB Controls: negative 14 days14 days rotations in the FST (IC50 288 µM) activity Controls: negative activity Controls: negative 14 days Reversed(IC50 the288 IL-1µM)β -relatedactivity CNS OH Restored decreased sucrose Reversedinflammation the IL-1 byβ-related markedly CNS Reversed the IL-1β-related CNS OH Restoredpreference decreased and increased sucrose inhibitinginflammation CUMS by-induced markedly PFC ReversedDR+ the IL-1β[60]-related CNS OH Oral gavage, 4 20–40 mg/kg Restored decreased sucrose inflammation by markedly ICR mouse CUMS, FST, TST immobilitypreference timeand increasedin the TST NF-inhibitingκB pathway CUMS and-induced modulating PFC inflammationDR+ by markedly[60] inhibiting Oralweeks gavage, 4 20–40(20 mg/kg) mg/kg preference and increased Restoredinhibiting CUMS decreased-induced sucrose PFC DR+ [60] DR+ [60] Oral gavage, 4 ICR mouse 20–40 mg/kg CUMS, FST, TST immobilityand FST in timemice insubjected the TST NLRP3NF-κB pathwayinflammasome and modulating activation CUMS-induced PFC NF-κB pathway Oralweeks gavage, ICR mouse (20 mg/kg) 20–40CUMS, mg/kg FST, TST immobility time in the TST NF-preferenceκB pathway and andincreased modulating weeks ICR mouse(20 mg/kg) andCUMS, FST toin FST, CUMSmice TST subjected NLRP3(activated inflammasome caspase 1) in activation CUMS and modulating NLRP3 inflammasome 4 weeks (20 mg/kg) and FST in mice subjected immobilityNLRP3 inflammasome time in the activation TST and to CUMS (activated caspasemice 1) in CUMS Controls:activation negative and (activated caspase 1) in Geraniol to CUMS FST(activated in mice caspase subjected 1) in toCUMS CUMS mice Controls:positive negative(fluoxetine) andCUMS mice Geraniol mice Controls: negative and MoleculesGeraniol 2017, 22 , 1290 positive (fluoxetine) 13 of 22 Controls: negative and Geraniol positive (fluoxetine) positive (fluoxetine)

DR+ [71] DR+ [71] Intraperitoneal, Swiss 25–50 mg/kg (25 OH Intraperitoneal, 25–50 mg/kgFST, TST Increased immobility time acute mouse Swiss mousemg/kg) FST, TST Increased immobility time acute (25 mg/kg)

Controls: negative and Isopulegol Controls: negative and Isopulegol positive (imipramine) positive (imipramine) DR− [46]

Restored increased Oral gavage, immobility time in rats Wistar rat 10 mg/kg FST Controls: negative and 15 days subjected to a model of positive (ketamine) neuropathic pain

Intraperitoneal, DR− [40] Limonene three times ICR mouse 100 mg/kg FST No effects Controls: negative and

within 24 h 1 positive (imipramine) DR+ [40] U-inverted curve Intraperitoneal, Controls: negative and 54.8–173.2 mg/kg three times ICR mouse FST Reduced immobility time positive (imipramine) OH (100 mg/kg) within 24 h The treatment reduced spontaneous locomotion The pretreatment with DR− Intraperitoneal, WAY100,635 (5-HT1A antagonist) three times ICR mouse 100 mg/kg FST Reduced immobility time and yohimbine (α2-antagonist) Controls: negative and [58] within 24 h prevented the positive (imipramine) Linalool antidepressant-like effects DR+ Intraperitoneal, Swiss 10–200 mg/kg TST Reduced immobility time Controls: negative and [59] acute mouse (100 mg/kg) positive (imipramine) Restored the CUMS-induced Reversed the decrease of reductions in hippocampal NE sucrose consumption, the and 5-HT levels; Reverted the Oral gavage, 3 15–30 mg/kg (15 hypolocomotion and the ICR mouse CUMS, FST, TST increased hippocampal DR+ [72] weeks mg/kg) increased immobile time in pro-inflammatory cytokines levels O the TST and FST in CUMS (IL-1β, IL-6, and TNFα) in CUMS mice mice;

Molecules 2017, 22, 1290 13 of 21 Molecules 2017, 22, 1290 13 of 22

Molecules 2017, 22, 1290 13 of 22 Table 2. Cont. Molecules 2017, 22, 1290 13 of 22 DR+ [71] Intraperitoneal, Swiss 25–50 mg/kg (25 OH FST, TST Increased immobility time acuteVia of mouse mg/kg) Dose Range Administration Tested and DR+ [71] Constituents Intraperitoneal, SwissAnimal 25–50 Specie mg/kg (25 Behavioral Test Observed Effects Mechanism of Action Observations Reference OH and Duration of MinimalFST, Active TST Increased immobility time acute mouse mg/kg) Controls: negative and Isopulegol Treatment Dose positive DR+(imipramine) [71] OH Intraperitoneal, Swiss 25–50 mg/kg (25 FST, TST Increased immobility time Controls: DRnegative− and [46] Isopulegol acute mouse mg/kg) positive (imipramine) Restored increased Restored increased immobility DR− [46] DR− [46] OralOral gavage, gavage, immobility time in rats time in rats subjected to a model Wistar rat Wistar rat 10 mg/kg 10 mg/kg FST FST Controls: negative and Isopulegol 15 days15 days subjected to a model of of neuropathic pain Restored increased positivepositive (imipramine) (ketamine) neuropathic pain Oral gavage, immobility time in rats DR− [46] Controls: negative and Wistar rat 10 mg/kg FST Controls: negative and 15 days subjected to a model of positive (ketamine) positive (ketamine) Restoredneuropathic increased pain Intraperitoneal,Oral gavage, immobility time in rats DR− [40] DR− [40] Intraperitoneal,Wistar rat 10 mg/kg FST Controls: negative and Limonene three15 days times ICR mouse 100 mg/kg FST subjected No toeffects a model of Controls: negative and Limonene three times within ICR mouse 100 mg/kg FST No effects positive (ketamine) Controls: negative and within 24 h neuropathic pain positive (imipramine) Intraperitoneal,24 h DR− [40] positive (imipramine) Limonene three times ICR mouse 100 mg/kg FST No effects Controls: DR+negative and [40]

within 24 h positiveU-inverted (imipramine) curve DR+ [40] Intraperitoneal,Intraperitoneal, Controls:DR negative− and [40] 54.8–173.2 mg/kg DR+ [40] Limonene threethree timestimes ICRICR mousemouse 100 mg/kg FSTFST Reduced No immobility effects time Controls:positive (imipramine)negative and U-inverted curve OH (100 mg/kg) U-inverted curve within 24 h Thepositive treatment (imipramine) reduced Intraperitoneal,Intraperitoneal, 54.8–173.2 mg/kg Controls: negative and Controls: negative and 54.8–173.2 mg/kg DR+ [40] threethree timestimes withinICR mouseICR mouse FST ReducedFST immobility time Reduced immobility time positivespontaneous (imipramine) positive (imipramine) OH (100 mg/kg) (100 mg/kg) U-invertedlocomotion curve within 24 h h The treatment reduced Intraperitoneal, The pretreatment with Controls: DRnegative− and The treatment reduced 54.8–173.2 mg/kg spontaneous Intraperitoneal,three times ICR mouse FST Reduced immobility time WAY100,635 (5-HT 1A antagonist) positive (imipramine) spontaneous OH (100 mg/kg) locomotion withinthree times 24 h ICR mouse 100 mg/kg FST Reduced immobility time and yohimbine (α2-antagonist) Controls: negative and [58] locomotion The pretreatment with The treatmentDR− reduced within 24 h prevented the positivespontaneous (imipramine) Linalool Intraperitoneal, WAY100,635 (5-HT1A antagonist) The pretreatment with WAY100,635 antidepressant-like effects locomotion three times ICR mouse 100 mg/kg FST Reduced immobility time and yohimbine (α2-antagonist) Controls:(5-HT negativeantagonist) and [58] and yohimbine DR− Intraperitoneal, DR+1A within 24 h The preventedpretreatment the with positive (imipramine)DR− Linalool Intraperitoneal,three times within Swiss ICR mouse10–200 mg/kg 100 mg/kg FST Reduced immobility time (α2-antagonist) prevented the [58] Linalool Intraperitoneal, TST Reduced immobility time WAY100,635 (5-HT 1A antagonist) Controls: negative and [59] acute mouse (100 mg/kg) antidepressant-like effects antidepressant-like effects Controls: negative and three times24 h ICR mouse 100 mg/kg FST Reduced immobility time and yohimbine (α2-antagonist) Controls:positive (imipramine)negative and [58] DR+ positive (imipramine) Intraperitoneal,within 24 h Swiss 10–200 mg/kg prevented the positive (imipramine) Linalool TST Reduced immobility time Restored the CUMS-induced Controls: negative and [59] acute mouse (100 mg/kg) Reversed the decrease of antidepressant-like effects reductions in hippocampal NE positive (imipramine) DR+ Intraperitoneal, 10–200 mg/kg (100 sucroseTST consumption, the Swiss mouse Reducedand 5-HT levels; immobility Reverted time the DR+ [59] Intraperitoneal,Oral gavage,acute 3 Swiss 15–3010–200 mg/kg mg/kg (15 mg/kg) hypolocomotion and the Restored the CUMS-induced Controls: negative and ICR mouse CUMS,TST FST, TST ReducedReversed immobility the decrease time of increased hippocampal Controls: DR+negative and [59][72] weeksacute mouse (100mg/kg) mg/kg) increased immobile time in reductions in hippocampal NE positive (imipramine) sucrose consumption, the pro-inflammatory cytokines levels positive (imipramine) O the TST and FST in CUMS and 5-HT levels; Reverted the Oral gavage, 3 15–30 mg/kg (15 hypolocomotion and the (IL-1Restoredβ, IL-6, the and CUMS-induced TNFα) in CUMS ICR mouse CUMS, FST, TST Reversed themice decrease of increased hippocampal RestoredDR+ the CUMS-induced[72] reductions weeks mg/kg) increased immobile time in reductions inmice; hippocampal NE O sucrose consumption, the pro-inflammatory cytokines levels the TST and FST in CUMS Reversedand 5-HT the levels; decrease Reverted of sucrose the in hippocampal NE and 5-HT levels; Oral gavage, 3 15–30 mg/kg (15 hypolocomotion and the (IL-1β, IL-6, and TNFα) in CUMS ICR mouse CUMS, FST, TST mice increasedconsumption, hippocampal the RevertedDR+ the increased[72] hippocampal weeks mg/kg) increased immobile time in mice; DR+ [72] Oral gavage, 15–30 mg/kg pro-inflammatoryhypolocomotion cytokines and levels the pro-inflammatory cytokines levels O ICR mouse theCUMS, TST and FST, FST TST in CUMS 3 weeks (15 mg/kg) (IL-1β, IL-6, and TNFα) in CUMS (IL-1β, IL-6, and TNFα) in CUMS mice; mice increased immobile time in the TST and FSTmice; in CUMS mice Inhibited the increased hippocampal nod-like receptor protein 3 (NLRP3) Controls: negative and Menthone inflammasome, and caspase-1 protein expression in CUMS mice positive (fluoxetine)

Molecules 2017, 22, 1290 14 of 21

Molecules 2017, 22, 1290 14 of 22 Molecules 2017, 22, 1290 14 of 22 Molecules 2017, 22, 1290 Table 2. Cont. 14 of 22 Inhibited the increased Inhibited the increased hippocampalInhibited thenod-like increased receptor Via of Dose Range hippocampal nod-like receptor hippocampalprotein nod-like3 (NLRP3) receptor Controls: negative and Menthone Administration Tested and protein 3 (NLRP3) Controls: negative and ConstituentsMenthone Animal Specie Behavioral Testinflammasome, Observedprotein 3 (NLRP3) and Effects caspase-1 Controls:positive negative(fluoxetine) Mechanism and of Action Observations Reference Menthone and Duration of Minimal Active inflammasome, and caspase-1 positive (fluoxetine) inflammasome,protein expression and incaspase-1 CUMS positive (fluoxetine) protein expression in CUMS Treatment Dose protein expressionmice in CUMS mice mice

Oral gavage, 1.0–10.0 µl/mL/kg1.0–10.0 µl/mL/kg DR+ [50] DR+ [50] OralOral gavage, acuteWistar ratsWistar 1.0–10.0 rats µl/mL/kg FST ReducedFST immobility time Reduced immobility time DR+ [50] Oralacute gavage, Wistar rats 1.0–10.0(1.0 µl/mL/kg) µl/mL/kg (1.0 µl/mL/kg)FST Reduced immobility time DR+ [50] acute Wistar rats (1.0 µl/mL/kg) FST Reduced immobility time MeO acute (1.0 µl/mL/kg) MeO MeO OMe OMe Methyl-eugenolOMe Controls: negative Methyl-eugenolMethyl-eugenol Controls: negative Controls: negative Methyl-eugenol Controls: negative

Intraperitoneal, DR− [40] Intraperitoneal, DR− [40] Intraperitoneal,three times ICR mouse 100 mg/kg FST No effects DR− [40] DR− [40] threeIntraperitoneal, times ICR mouse 100 mg/kg FST No effects withinthree times 24 h ICR mouse 100 mg/kg FST No effects threewithin times 24 h within ICR mouse 100 mg/kg FST No effects within 24 h Controls: negative and α-Pinene 24 h Controls: negative and α-Pinene Controls:positive (imipramine) negative and α-Pinene positive (imipramine) Controls: negative and α-Pinene positive (imipramine)DR+ [40] DR+ [40] positive (imipramine) Controls:DR+ negative and [40] Intraperitoneal, Controls: negative and Intraperitoneal, 54.8–173.2 mg/kg Controls:positive (imipramine) negative and DR+ [40] Intraperitoneal,three times ICR mouse 54.8–173.2 mg/kg FST Reduced immobility time positive (imipramine) three times ICR mouse 54.8–173.2(100 mg/kg) mg/kg FST Reduced immobility time Thepositive treatment (imipramine) reduced withinthree times 24 h ICR mouse (100 mg/kg) FST Reduced immobility time The treatment reduced Controls: negative and within 24 h (100 mg/kg) Thethe treatment spontaneous reduced withinIntraperitoneal, 24 h the spontaneous 54.8–173.2 mg/kg thelocomotion spontaneous positive (imipramine) three times within ICR mouse FST Reduced immobility time locomotion (100 mg/kg) The pretreatment with locomotionDR− The treatment reduced 24 h The pretreatment with DR− TheWAY100,635 pretreatment (5-HT with1A DR− the spontaneous WAY100,635 (5-HT1A Intraperitoneal, antagonist),WAY100,635 propranolol (5-HT1A Intraperitoneal, antagonist), propranolol locomotion β-Pinene Intraperitoneal,three times ICR mouse 100 mg/kg FST Reduced immobility time (antagonist),β-antagonist), propranolol DSP-4 (NE Controls: negative and [58] ββ-Pinene-Pinene three times ICR mouse 100 mg/kg FST Reduced immobility time (β-antagonist), DSP-4 (NE Controls: negative and [58] β-Pinene withinthree times 24 h ICR mouse 100 mg/kg FST Reduced immobility time neurotoxin),(β-antagonist), SCH23390 DSP-4 (NE (D1 Controls:positiveThe (imipramine) negative pretreatment and with[58] WAY100,635 within 24 h neurotoxin), SCH23390 (D1 positive (imipramine) within 24 h neurotoxin),antagonist) preventedSCH23390 the(D1 positive(5-HT (imipramine)1A antagonist), propranolol DR− Intraperitoneal, antagonist) prevented the antagonist)anti-immobility prevented effect the (β-antagonist), DSP-4 (NE neurotoxin), three times within ICR mouse 100 mg/kg FST Reducedanti-immobility immobility effect time [58] Oral gavage, 7 ICR mouse 60–120 mg/kg LPS-induced Reversed increased in anti-immobility Reversed the reduced effect SCH23390 DR+ (D1 antagonist) [70] prevented the Oral gavage,24 h 7 ICR mouse 60–120 mg/kg LPS-induced Reversed increased in Reversed the reduced DR+ [70] Oral gavage, 7 ICR mouse 60–120 mg/kg LPS-induced Reversed increased in Reversed the reduced DR+ anti-immobility [70] effect Controls: negative and positive (imipramine)

Reversed the reduced concentrations of LPS-induced 5-HT and NE, and attenuated DR+ [70] 60–120 mg/kg Reversed increased in immobility Oral gavage, 7 days ICR mouse depressant-like LPS-induced increases of serum protein (60 mg/kg) time in the FST and TST in behavior, FST and TST LPS-treated mice levels and prefrontal cortex mRNA of TNF-α and IL-6 Controls: negative and positive (fluoxetine)

0.1–10% dropped Reduced immobility time in DR+ [57] on the area Perillaldehyde Inhalation, 9 days ddY mouse CUMS, FST naïve mouse and reversed between eyes and increased immobility time in Controls: negative and nose (1%) CUMS mice positive (minalcipran)

O O (CH2)5CH3

1

Molecules 2017, 22, 1290 15 of 21 Molecules 2017, 22, 1290 15 of 22 Molecules 2017, 22, 1290 15 of 22 days (60 mg/kg) depressant-like immobility time in the FST concentrations of 5-HT and NE, days (60 mg/kg) depressant-likebehavior, FST immobilityand TST in time LPS-treated in the FST concentrationsand attenuated of LPS-induced5-HT and NE, Table 2. Cont. Controls: negative and behavior,and TST FST and TST inmice LPS-treated increasesand attenuated of serum LPS-induced protein levels Controls:positive negative(fluoxetine) and and TST mice increasesand prefrontal of serum cortex protein mRNA levels of positive (fluoxetine) Via of Dose Range and prefrontalTNF-α cortexand IL-6 mRNA of Reduced immobility time in TNF-α and IL-6 DR+ [57] Administration 0.1–10% dropped Tested and Constituents Inhalation, ddY Animal Specie ReducednaïveBehavioral mouse immobility and Test reversed time in Observed EffectsDR+ Mechanism of[57] Action Observations Reference Perillaldehyde and Duration of on0.1–10% the area dropped betweenMinimal CUMS, Active FST Controls: negative and Inhalation,9 days mouseddY naïveincreased mouse immobility and reversed time Perillaldehyde Treatment oneyes the and area nose between (1%) DoseCUMS, FST Controls:positive (minalcipran) negative and 9 days mouse increasedin CUMS immobility mice time eyes and nose (1%) positive (minalcipran) in CUMS mice

Restored increased Oral gavage, Restored increased immobility DR− [46] DR− [46] Oral gavage, once immobilityRestored increasedtime in rats Oralonce gavage, daily, Wistar rat 10 mg/kg 10 mg/kg FST time in rats subjected to a model DR− [46] Wistar rat immobilitysubjectedFST to time a model in rats of oncedaily,15 daysdaily, 15 daysWistar rat 10 mg/kg FST subjectedneuropathic to a model pain of of neuropathic pain 15 days neuropathic pain Controls: negative and α-Phellandrene Controls: negative and α-Phellandrene Controls:positive negative (ketamine) and α-Phellandrene positive (ketamine) Restored the CUMS-induced positive (ketamine) reductions in hippocampal NE reductionsRestored the in hippocampalCUMS-induced NE Restored the CUMS-induced reductions and 5-HT; Reverted the reductions in hippocampal NE in hippocampal NE and 5-HT; Reverted Reversed the decrease of increasedand 5-HT; hippocampal Reverted themRNA theDR+ increased hippocampal[73] mRNA of sucroseReversed consumption, the decrease theof increasedof pro-inflammatory hippocampal cytokines mRNA OH Reversed the decrease of sucrose pro-inflammatoryDR+ cytokines[73] (IL-1β, IL-6, DR+ [73] OralOral gavage, gavage, 15–30 mg/kg 15–30 mg/kg losssucrose of body consumption, weight, and the the (IL-1of pro-inflammatoryβ, IL-6, and TNFα cytokines) in CUMS OH ICR mouseICR mouse CUMS, TST, FST CUMS, TST, FST consumption, the loss of body α Oral3 weeks gavage, 15–30(15 mg/kg) mg/kg (15 mg/kg) lossincreased of body immobile weight, andtime the in (IL-1mice;β, InhibitedIL-6, and theTNF activationα) in CUMS of and TNF ) in CUMS mice; Inhibited the 3 weeks ICR mouse CUMS, TST, FST weight, and the increased 3 weeks (15 mg/kg) increasedthe TST immobile and FST time in in mice;nod-like Inhibited receptor the activation protein 3 of activation of nod-like receptor protein 3 immobile time in the TST and the TSTCUMS and mice FST in (NLRP3)nod-like inflammasome receptor protein and 3 its (NLRP3) inflammasome and its adaptor, adaptor,FST in and CUMS subsequently mice Controls: negative and Thymol CUMS mice (NLRP3)adaptor, inflammasome and subsequently and its and subsequently decreased the Controls: negative and Thymol decreased the expression of Controls:positive negative(fluoxetine) and Thymol adaptor, and subsequently expression of caspase-1 positive (fluoxetine) decreasedcaspase-1 the expression of positive (fluoxetine) caspase-1 O O A significant elevation of 5-HT wholeA significant brain levels elevation was observed; of 5-HT A significantDR− elevation[74] of 5-HT whole DR− [74] Intraperitoneal, Swiss Reduced immobility time in O Intraperitoneal, 20 mg/kg FST, TST wholeReducedIncreased brain glutathione immobility levels was levelsobserved; time and in brainDR− levels was observed;[74] Increased Intraperitoneal,acute mouseSwiss Swiss mouse 20 mg/kg ReducedFST, immobilityboth TST tests time in acute 20 mg/kg FST, TST Increaseddecreased glutathioneboth TBARS tests levels levels in theand glutathione levels and decreased TBARS O acute mouse both tests decreasedwhole TBARS brain levels in the levels in the whole brain whole brain Controls: negative and MoleculesThymoquinone 2017, 22, 1290 16 of 22 Controls: negative and Thymoquinone Controls:positive negative(fluoxetine) and Thymoquinone positive (fluoxetine) positive (fluoxetine) CHO

Swiss DR+ [75] DR+ [75] Oral gavage, Reduced immobility time mouse Swiss mouse10–100 mg/kg H3CO Oralacute gavage,and 10 acute 10–100 mg/kgFST, TST under acute and chronic Reduced immobility time under (male and (male and(10 mg/kg) FST, TST anddays 10 days (10 mg/kg) treatments acute and chronic treatments OH female) female) Controls: negative and Controls: negative and Vanillin positive (fluoxetine Vanillin positive (fluoxetine and imipramine) and imipramine) FST: forced swimming test; TST: tail suspension test; OFT: open field test; CUMS: Chronic unpredictable mild stress; DR+: dose/concentration response design; DR−-: FST:absence forced of dose/concentration swimming test; response; TST: tail 5-HT: suspension serotonin; DA: test; dopamine; OFT: open NE: noradrenaline. field test; CUMS: Chronic unpredictable mild stress; DR+: dose/concentration response design; DR−-: absence of dose/concentration response; 5-HT: serotonin; DA: dopamine; NE: noradrenaline.

Molecules 2017, 22, 1290 16 of 21

6. Constituents from Essential Oils with Antidepressant-Like Activity The effects of isolated compounds from essential oils in the rodent behavior are summarized in Table2.

6.1. Isolated Constituents with Proposed Mechanisms of Antidepressant Action The most studied isolated compounds are eugenol [61,62] and linalool [40,58,59]. Studies suggest robust antidepressant-like actions as demonstrated in distinct behavioral tests (FST and TST) performed in different labs around the world. The main target of the antidepressant action of eugenol is the MAO enzyme [62]. This compound preferentially inhibits the MAOA activity, and after chronic administrations increases the neurotrophic factor, BDNF, a mechanism of action shared with conventional antidepressants [4]. Concerning linalool, main constituent of the extracted lavender and clary sage oil [31,76], acute studies suggestive of antidepressant actions support the activation of monoamine 5-HT1A and α2-receptors [58]. Other isolated constituents from essential oils that induce antidepressant-like actions possibly mediated by monoamines are L-menthone [72], perillaldehyde [57], thymol [73] and thymoquinone [74]. These compounds increase monoamines in the brain, a mechanism of action similar to classical antidepressants. Studies showed that carvacrol and β-pinene induce antidepressant-like actions in behavioral despair assays, e.g., FST and TST [58,68]. The acute treatment with these isolated constituents decrease the immobility time, an effect reversed by the pretreatment with SCH23390, a dopamine D1 antagonist [58,68]. The antidepressant effects of β-pinene were also blocked by 5-HT1A antagonist, β-antagonist and DSP-4, a noradrenergic neurotoxin [58]. By contrast, the pretreatment with prazosin, a α1-receptor antagonist, yohimbine, a α2-receptor antagonist, and PCPA, a 5-HT synthesis inhibitor, did not affect the antidepressant effects of carvacrol [68]. These experimental data suggest that β-pinene seems to evoke antidepressant actions dependent on dopaminergic, serotoninergic and noradrenergic systems, while carvacrol displays antidepressant activity mainly mediated by dopaminergic system. Some other promising isolated compounds from essential oils, such as L-menthone [72], thymol [73] and geraniol [47] induce antidepressant-like effects in rodents and the mechanisms of these actions were partially described. For these compounds, potential anti-inflammatory effects may be involved and/or mediating the antidepressant actions. A growing number of preclinical and clinical studies have demonstrated an association between concentrations of pro-inflammatory cytokines—mainly interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and depressive symptoms. In addition, mounting evidence has shown a concomitant reduction in both depressive symptoms and pro-inflammatory cytokine concentrations following treatment with anti-inflammatory drugs [77]. In this view, L-menthone, thymol and geraniol inhibited IL-1β, IL-6 and TNFα cytokines and other pro-inflammatory intracellular signaling, such as NF-κB, NLRP3 and caspase 1, usually increased by stress. Interestingly, the antidepressant fluoxetine could restore CUMS-induced depression-like behavior in mice by significantly decreasing the level of NLRP3 and caspase 1 [77]. Cinnamic aldehyde reversed the loss of sucrose preference in CUMS rats and also reversed the increased COX-2 hippocampal expression and enzyme activity. However, no behavioral effects have been observed when mice injected with cinnamic aldehyde were subjected in the FST [78]. Restoration of PGE2 concentration in frontal cortex and hippocampus of stressed rats was also found in cinnamic aldehyde-treated animals [69]. It is interesting to mention that some of these compounds display notable anti-inflammatory actions, such as thymol [79] and geraniol [80], while others induce peripheral pro-inflammatory effects, e.g., cinnamic aldehyde [81]. Taken together, it is still unknown if a putative central nervous system anti-inflammatory effect is required for the antidepressant action of conventional drugs. However, further studies aimed to identify the molecular site of action of these compounds are mandatory. Considering that most isolated constituents share a monoaminergic and/or pro-inflammatory mechanism of antidepressant action, it could be suggested that these compounds may present some Molecules 2017, 22, 1290 17 of 21 chemical similarities, thus supporting an interaction with the same molecular site of action. However, the diversity of chemical structures of these compounds makes it difficult to establish a chemical template determining the antidepressant activity. This fact can be explained due to possible distinct molecular sites of action, or formation of psychoactive metabolite products.

6.2. Isolated Constituents without Antidepressant Mechanism of Action Vanillin a constituent of essential oils used in cooking because of its pleasant odor and flavor to the food. This constituent reduced immobility duration in the FST and TST in mice after oral acutely administration. Chronic oral treatment with vanillin reduced immobility time in mice at significantly lower levels when compared to fluoxetine [75]. α-Asarone and β-asarone are found in several essential oils, including as major components from the rhizome essential oil of Acorus tatarinowii Schott. These isolated compounds as well the Acorus tatarinowii Schott essential oil displays antidepressant-like effect in the FST and TST [33]. No details about the antidepressant mechanisms of action of these isolated constituents were already proposed. Two other isolated constituents, limonene and α-phellandrene, reversed the depressant-like behavior and reduced nociceptive responses in rodents subjected to a model of neurophatic pain [46]. These effects are quite interesting and should be further investigated, since chronic pain is a common comorbidity of major depressive patients.

7. Conclusions The antidepressant effects of essential oils and their constituents are very promising but they are still at the preliminary stages. Few clinical trials have been performed until now, and most of them are aimed for testing the effects of lavender oil. Importantly, the preclinical effects of lavender oil on rodents were superficially studied, and there is no suggestion of mechanism of action for this antidepressant effect. By contrast, some essential oil constituents display promising antidepressant effects by involving monoamine neurotransmission. With respect to the attribution of the antidepressant effect of a whole essential oil to one single constituent, the overall conclusion remains that the diversity of chemically active constituents of essential oils can be an advantage in the treatment of depression, since more than one compound with positive effects on depression can evoke synergic actions. Finally, the importance of these preclinical observations for the clinical overall picture of depression still needs to be addressed through further research. Future clinical trials will give scientific support for the employment of essential oils with potential antidepressant actions as real options for the treatment of depressive states.

Acknowledgments: This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Author Contributions: R.H.N.S. and E.F.d.S. revised the literature and prepared the tables. D.P.d.S and E.C.G. prepared and revised the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

References

1. American Psychiatric Press (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Psychiatric Press: Washington, DC, USA, 2013. 2. Ferrari, A.J.; Somerville, A.J.; Baxter, A.J.; Norman, R.; Patten, S.B.; Vos, T.; Whiteford, H.A. Global variation in the prevalence and incidence of major depressive disorder: A systematic review of the epidemiological literature. Psychol. Med. 2013, 43, 471–481. [CrossRef][PubMed] 3. Nemeroff, C.B.; Owens, M.J. Treatment of mood disorders. Nat. Neurosci. 2002, 5, 1068–1070. [CrossRef] [PubMed] 4. Castrén, E. Is mood chemistry? Nat. Rev. Neurosci. 2005, 6, 241–246. [CrossRef][PubMed] 5. Björkholm, C.; Monteggia, L.M. BDNF—A key transducer of antidepressant effects. Neuropharmacology 2016, 102, 72–79. [CrossRef][PubMed] Molecules 2017, 22, 1290 18 of 21

6. Santarelli, L.; Saxe, M.; Gross, C.; Sunget, A.; Battaglia, F.; Dulawa, S.; Weisstaub, N.; Lee, J.; Duman, R.; Arancio, O.; et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003, 301, 805–809. [CrossRef][PubMed] 7. Berton, O.; Nestler, E.J. New approaches to antidepressant drug discovery: Beyond monoamines. Nat. Rev. Neuroscience 2006, 7, 137–151. [CrossRef][PubMed] 8. Bezerra, D.P.; Soares, A.K.; De Sousa, D.P. Overview of the role of vanillin on redox status and cancer development. Oxid. Med. Cell. Longev. 2016, 2016, 9734816. [CrossRef][PubMed] 9. Souto-Maior, F.N.; Fonsêca, D.V.; Salgado, P.R.; Monte, L.O.; de Sousa, D.P.; de Almeida, R.N. Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide. Pharm. Biol. 2017, 55, 63–67. [CrossRef] [PubMed] 10. De Sousa, D.P.; Lima, T.C.; Steverding, D. Evaluation of antiparasitc activity of Mentha crispa essential oil, its major constituent rotundifolone and analogues against Trypanosoma brucei. Planta Med. 2016, 82, 1346–1350. [CrossRef][PubMed] 11. De Sousa, D.P.; de Almeida Soares Hocayen, P.; Andrade, L.N.; Andreatini, R. A Systematic review of the anxiolytic-like effects of essential oils in animal models. Molecules 2015, 20, 18620–18660. [CrossRef] [PubMed] 12. Kim, W.; Hur, M.H. Inhalation effects of aroma essential oil on quality of sleep for shift nurses after night work. J. Korean Acad. Nurs. 2016, 46, 769–779. [CrossRef][PubMed] 13. Lytle, J.; Mwatha, C.; Davis, K.K. Effect of lavender aromatherapy on vital signs and perceived quality of sleep in the intermediate care unit: A pilot study. Am. J. Crit. Care 2014, 23, 24–29. [CrossRef][PubMed] 14. Press-Sandler, O.; Freud, T.; Volkov, I.; Peleg, R.; Press, Y. Aromatherapy for the Treatment of Patients with Behavioral and Psychological Symptoms of Dementia: A Descriptive Analysis of RCTs. J. Altern. Complement. Med. 2016, 22, 422–428. [CrossRef][PubMed] 15. Forrester, L.T.; Maayan, N.; Orrell, M.; Spector, A.E.; Buchan, L.D.; Soares-Weiser, K. Aromatherapy for dementia. Cochrane Database Syst. Rev. 2014, 2, CD003150. 16. Dong, S.; Jacob, T.J. Combined non-adaptive light and smell stimuli lowered blood pressure, reduced heart rate and reduced negative affect. Physiol. Behav. 2016, 156, 94–105. [CrossRef][PubMed] 17. Kasper, S.; Anghelescu, I.; Dienel, A. Efficacy of orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep—A randomized, placebo-controlled trial. Eur. Neuropsychopharmacol. 2015, 25, 1960–1967. [CrossRef][PubMed] 18. Cordell, B.; Buckle, J. The effects of aromatherapy on nicotine craving on a U.S. campus: A small comparison study. J. Altern. Complement. Med. 2013, 19, 709–713. [CrossRef][PubMed] 19. Uehleke, B.; Schaper, S.; Dienel, A.; Schlaefke, S.; Stange, R. Phase II trial on the effects of Silexan in patients with neurasthenia, post-traumatic stress disorder or somatization disorder. Phytomedicine 2012, 19, 665–671. [CrossRef][PubMed] 20. Jimbo, D.; Kimura, Y.; Taniguchi, M.; Inoue, M.; Urakami, K. Effect of aromatherapy on patients with Alzheimer’s disease. Psychogeriatrics 2009, 9, 173–179. [CrossRef][PubMed] 21. De Sousa, D.P. Analgesic-like activity of essential oils constituents. Molecules 2011, 16, 2233–2252. [CrossRef] [PubMed] 22. De Sousa, D.P. Bioactive Essential Oils and Cancer; Springer International Publishing: New York, NY, USA, 2015. 23. Oliveira, F.A.; Andrade, L.N.; De Sousa, E.B.; De Sousa, D.P. Anti-ulcer activity of essential oil constituents. Molecules 2014, 19, 5717–5747. [CrossRef][PubMed] 24. Sobral, M.V.; Xavier, A.L.; Lima, T.C.; De Sousa, D.P. Antitumor activity of monoterpenes found in essential oils. Sci. World J. 2014, 2014, 953451. [CrossRef][PubMed] 25. Yim, V.W.; Ng, A.K.; Tsang, H.W.; Leung, A.Y. A review on the effects of aromatherapy for patients with depressive symptoms. J. Altern. Complement. Med. 2009, 15, 187–195. [CrossRef][PubMed] 26. Lee, Y.L.; Wu, Y.; Tsang, H.W.; Leung, A.Y.; Cheung, W.M. A systematic review on the anxiolytic effects of aromatherapy in people with anxiety symptoms. J. Altern. Complement. Med. 2011, 17, 101–108. [CrossRef] [PubMed] 27. Setzer, W.N. Essential oils and anxiolytic aromatherapy. Nat. Prod. Commun. 2009, 4, 1305–1316. [PubMed] Molecules 2017, 22, 1290 19 of 21

28. Fibler, M.; Quante, A. A case series on the use of lavendula oil capsules in patients suffering from major depressive disorder and symptoms of psychomotor agitation, insomnia and anxiety. Complement. Ther. Med. 2014, 22, 63–69. 29. Diego, M.A.; Jones, N.A.; Field, T.; Hernandez-Reif, M.; Schanberg, S.; Kuhn, C.; McAdam, V.; Galamaga, R.; Galamaga, M. Aromatherapy positively affects mood, EEG patterns falertness and math computations. Int. J. Neurosci. 1998, 96, 217–224. [CrossRef][PubMed] 30. Conrad, P.; Adams, C. The effects of clinical aromatherapy for anxiety and depression in the high risk postpartum woman—A pilot study. Complement. Ther. Clin. Pract. 2012, 18, 164–168. [CrossRef][PubMed] 31. Lee, K.B.; Cho, E.; Kang, Y.S. Changes in 5-hydroxytryptamine and cortisol plasma levels in menopausal women after inhalation of clary sage oil. Phytother. Res. 2014, 28, 1599–1605. [CrossRef][PubMed] 32. Komori, T.; Fujiwara, R.; Tanida, M.; Nomura, J.; Yokoyama, M.M. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation 1995, 2, 174–180. [CrossRef][PubMed] 33. Han, P.; Han, T.; Peng, W.; Wang, X.R. Antidepressant-like effects of essential oil and asarone, a major essential oil component from the rhizome of Acorus tatarinowii. Pharm. Biol. 2013, 51, 589–594. [CrossRef] [PubMed] 34. Park, H.J.; Lim, E.J.; Zhao, R.J.; Oh, S.R.; Jung, J.W.; Ahn, E.M.; Lee, E.S.; Koo, J.S.; Kim, H.Y.; Chang, S.; et al. Effect of the fragrance inhalation of essential oil from Asarum heterotropoides on depression-like behaviors in mice. BMC Complement. Altern. Med. 2015, 15, 43. [CrossRef][PubMed] 35. Komori, T.; Fujiwara, R.; Tanida, M.; Nomura, J. Potential antidepressant effects of lemon odor in rats. Eur. Neuropsychopharmacol. 1995, 5, 477–480. [CrossRef] 36. Komiya, M.; Takeuchi, T.; Harada, E. Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice. Behav. Brain Res. 2006, 172, 240–249. [CrossRef][PubMed] 37. Lopes, C.L.M.; Sá, C.G.; de Almeida, A.A.; da Costa, J.P.; Marques, T.H.; Feitosa, C.M.; Saldanha, G.B.; de Freitas, R.M. Sedative, anxiolytic and antidepressant activities of Citrus limon (Burn) essential oil in mice. Die Pharm. 2011, 66, 623–627. 38. Victoria, F.N.; de Siqueira, A.B.; Savegnago, L.; Lenardão, E.J. Involvement of serotoninergic and adrenergic systems on the antidepressant-like effect of E. uniflora L. leaves essential oil and further analysis of its antioxidant activity. Neurosci. Lett. 2013, 544, 105–109. [CrossRef][PubMed] 39. Seol, G.H.; Shim, H.S.; Kim, P.J.; Moon, H.K.; Lee, K.H.; Shim, I.; Suh, S.H.; Min, S.S. Antidepressant-like effect of Salvia sclarea is explained by modulation of dopamine activities in rats. J. Ethnopharmacol. 2010, 130, 187–190. [CrossRef][PubMed] 40. Guzmán-Gutiérrez, S.L.; Gómez-Cansino, R.; García-Zebadúa, J.C.; Jiménez-Pérez, N.C.; Reyes-Chilpa, R. Antidepressant activity of Litsea glaucescens essential oil: Identification of β-pinene and linalool as active principles. J. Ethnopharmacol. 2012, 143, 673–679. [CrossRef][PubMed] 41. Lim, W.C.; Seo, J.M.; Lee, C.I.; Pyo, H.B.; Lee, B.C. Stimulative and sedative effects of essential oils upon inhalation in mice. Arch. Pharm. Res. 2005, 28, 770–774. [CrossRef][PubMed] 42. Ji, W.W.; Li, R.P.; Li, M.; Wang, S.Y.; Zhang, X.; Niu, X.X.; Li, W.; Yan, L.; Wang, Y.; Fu, Q.; et al. Antidepressant-like effect of essential oil of Perilla frutescens in a chronic, unpredictable, mild stress-induced depression model mice. Chin. J. Nat. Med. 2014, 12, 753–759. [CrossRef] 43. Yi, L.T.; Li, J.; Geng, D.; Liu, B.B.; Fu, Y.; Tu, J.Q.; Liu, Y.; Weng, L.J. Essential oil of Perilla frutescens-induced change in hippocampal expression of brain-derived neurotrophic factor in chronic unpredictable mild stress in mice. J. Ethnopharmacol. 2013, 147, 245–253. [CrossRef][PubMed] 44. Machado, D.G.; Cunha, M.P.; Neis, V.B.; Balen, G.O.; Colla, A.; Bettio, L.E.B.; Oliveira, A.; Pazini, F.L.; Dalmarco, J.B.; Simionatto, E.L.; et al. Antidepressant-like effects of fractions, essential oil, carnosol and betulinic acid isolated from Rosmarinus officinalis L. Food Chem. 2013, 136, 999–1005. [CrossRef][PubMed] 45. Viana, C.C.S.; Oliveira, P.A.; Brum, L.F.S.; Picada, J.N.; Pereira, P. Gamma-decanolactone effect on behavioral and genotoxic parameters. Life Sci. 2007, 80, 1014–1019. [CrossRef][PubMed] 46. Piccinelli, A.C.; Santos, J.A.; Konkiewitz, E.C.; Oesterreich, S.A.; Formagio, A.S.; Croda, J.; Ziff, E.B.; Kassuya, C.A. Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model. Nutr. Neurosci. 2015, 18, 217–224. [CrossRef][PubMed] Molecules 2017, 22, 1290 20 of 21

47. Liu, B.B.; Luo, L.; Liu, X.L.; Geng, D.; Li, C.F.; Chen, S.M.; Chen, X.M.; Yi, L.T.; Liu, Q. Essential oil of Syzygium aromaticum reverses the deficits of stress-induced behaviors and hippocampal p-ERK/p-CREB/brain-derived neurotrophic factor expression. Planta Med. 2015, 81, 185–192. [CrossRef][PubMed] 48. Duan, D.; Chen, L.; Yang, X.; Tu, Y.; Jiao, S. Antidepressant-like effect of essential oil isolated from Toona ciliata Roem. var. yunnanensis. J. Nat. Med. 2015, 69, 191–197. [CrossRef][PubMed] 49. Sah, S.P.; Mathela, C.S.; Chopra, K. Involvement of nitric oxide (NO) signalling pathway in the antidepressant activity of essential oil of Valeriana wallichii Patchouli alcohol chemotype. Phytomedicine 2011, 18, 1269–1275. [CrossRef][PubMed] 50. Norte, M.C.; Cosentino, R.M.; Lazarini, C.A. Effects of methyl-eugenol administration on behavioral models related to depression and anxiety, in rats. Phytomedicine 2005, 12, 294–298. [CrossRef][PubMed] 51. Waters, R.P.; Rivalan, M.; Bangasser, D.A.; Deussing, J.M.; Ising, M.; Wood, S.K.; Holsboer, F.; Summers, C.H. Evidence for the role of corticotropin-releasing factor in major depressive disorder. Neurosci. Biobehav. Rev. 2015, 58, 63–78. [CrossRef][PubMed] 52. Bahi, A.; Al Mansouri, S.; Al Memari, E.; Al Ameri, M.; Nurulain, S.M.; Ojha, S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol. Behav. 2014, 135, 119–124. [CrossRef][PubMed] 53. Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J.Z.; Xie, X.Q.; Altmann, K.H.; Karsak, M.; Zimmer, A. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. USA 2008, 105, 9099–9104. [CrossRef] [PubMed] 54. Marco, E.M.; García-Gutiérrez, M.S.; Bermúdez-Silva, F.J.; Moreira, F.A.; Guimarães, F.; Manzanares, J.; Viveros, M.P. Endocannabinoid system and psychiatry: In search of a neurobiological basis for detrimental and potential therapeutic effects. Front. Behav. Neurosci. 2011, 5, 63. [CrossRef][PubMed] 55. Bhattacharya, A.; Derecki, N.C.; Lovenberg, T.W.; Drevets, W.C. Role of neuro-immunological factors in the pathophysiology of mood disorders. Psychopharmacology 2016, 233, 1623–1636. [CrossRef][PubMed] 56. Ling, Y.Z. Analysis of the volatile oil of Perilla frutescens drawing with two kinds of method by GC/MS. Chin. Condiment 2005, 30, 18–30. 57. Ito, N.; Nagai, T.; Oikawa, T.; Yamada, H.; Hanawa, T. Antidepressant-like effect of l-perillaldehyde in stress-induced depression-like model mice through regulation of the olfactory nervous system. Evid. Based Complement. Altern. Med. 2011, 2011, 512697. [CrossRef][PubMed] 58. Guzmán-Gutiérrez, S.L.; Bonilla-Jaime, H.; Gómez-Cansino, R.; Reyes-Chilpa, R. Linalool and β-pinene exert their antidepressant-like activity through the monoaminergic pathway. Life Sci. 2015, 128, 24–29. [CrossRef] [PubMed] 59. Coelho, V.; Mazzardo-Martins, L.; Martins, D.F.; Santos, A.R.; da Silva Brum, L.F.; Picada, J.N.; Pereira, P. Neurobehavioral and genotoxic evaluation of (-)-linalool in mice. J. Nat. Med. 2013, 67, 876–880. [CrossRef] [PubMed] 60. Deng, X.Y.; Xue, J.S.; Li, H.Y.; Ma, Z.Q.; Fu, Q.; Qu, R.; Ma, S.P. Geraniol produces antidepressant-like effects in a chronic unpredictable mild stress mice model. Physiol. Behav. 2015, 152, 264–271. [CrossRef][PubMed] 61. Irie, Y.; Itokazu, N.; Anjiki, N.; Ishige, A.; Watanabe, K.; Keung, W.M. Eugenol exhibits antidepressant-like activity in mice and induces expression of metallothionein- III in the hippocampus. Brain Res. 2004, 1011, 243–246. [CrossRef][PubMed] 62. Tao, G.; Irie, Y.; Li, D.J.; Keung, W.M. Eugenol and its structural analogs inhibit monoamine oxidase A and exhibit antidepressant-like activity. Bioorg. Med. Chem. 2005, 13, 4777–4788. [CrossRef][PubMed] 63. Brocardo, P.S.; Budni, J.; Lobato, K.R.; Kaster, M.P.; Rodrigues, A.L. Antidepressant-like effect of folic acid: Involvement of NMDA receptors andl-arginine–nitric oxide–cyclic guanosine monophosphate pathway. Eur. J. Pharmacol. 2008, 598, 37–42. [CrossRef][PubMed] 64. Jesse, C.R.; Bortolatto, C.F.; Savegnago, L.; Rocha, J.B.; Nogueira, C.W. Involvement of l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. Prog. Neuropsychopharmacol. Biol. Psychiatry 2008, 32, 1838–1843. [CrossRef][PubMed] 65. Crespi, F. The selective serotonin reuptake inhibitor fluoxetine reduces striatal in vivo levels of voltammetric nitric oxide (NO): A feature of its antidepressant activity? Neurosci. Lett. 2010, 470, 95–99. [CrossRef] [PubMed] Molecules 2017, 22, 1290 21 of 21

66. Dhir, A.; Kulkarni, S.K. Involvement of l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of venlafaxine in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 2007, 31, 921–925. [CrossRef][PubMed] 67. Ghasemi, M.; Montaser-Kouhsari, L.; Shafaroodi, H.; Nezami, B.G.; Ebrahimi, F.; Dehpour, A.R. NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test. Psychopharmacology 2009, 206, 325–333. [CrossRef][PubMed] 68. Melo, F.H.; Moura, B.A.; de Sousa, D.P.; de Vasconcelos, S.M.; Macedo, D.S.; Fonteles, M.M.; Viana, G.S.; de Sousa, F.C. Antidepressant-like effect of carvacrol (5-Isopropyl-2-methylphenol) in mice: Involvement of dopaminergic system. Fundam. Clin. Pharmacol. 2011, 25, 362–367. [CrossRef][PubMed] 69. Yao, Y.; Huang, H.Y.; Yang, Y.X.; Guo, J.Y. Cinnamic aldehyde treatment alleviates chronic unexpected stress-induced depressive-like behaviors via targeting cyclooxygenase-2 in mid-aged rats. J. Ethnopharmacol. 2015, 162, 97–103. [CrossRef][PubMed] 70. Ji, W.W.; Wang, S.Y.; Ma, Z.Q.; Li, R.P.; Li, S.S.; Xue, J.S.; Li, W.; Niu, X.X.; Yan, L.; Zhang, X.; et al. Effects of perillaldehyde on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol. Biochem. Behav. 2014, 116, 1–8. [CrossRef][PubMed] 71. Silva, M.I.G.; Aquino Neto, M.R.; Neto, P.F.T.; Moura, B.A.; do Amaral, J.F.; de Sousa, D.P.; Vasconcelos, S.M.M.; de Sousa, F.C.F. Central nervous system activity of acute administration of isopulegol in mice. Pharmacol. Biochem. Behav. 2007, 88, 141–147. [CrossRef][PubMed] 72. Xue, J.; Li, H.; Deng, X.; Ma, Z.; Fu, Q.; Ma, S. L-Menthone confers antidepressant-like effects in an unpredictable chronic mild stress mouse model via NLRP3 inflammasome-mediated inflammatory cytokines and central neurotransmitters. Pharmacol. Biochem. Behav. 2015, 134, 42–48. [CrossRef][PubMed] 73. Deng, X.Y.; Li, H.Y.; Chen, J.J.; Li, R.P.; Qu, R.; Fu, Q.; Ma, S.P. Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice. Behav. Brain Res. 2015, 291, 12–19. [CrossRef][PubMed] 74. Aquib, M.; Najmi, A.K.; Akhtar, M. Antidepressant effect of thymoquinone in animal models of depression. Drug Res. 2015, 65, 490–494. [CrossRef][PubMed] 75. Shoeb, A.; Chowta, M.; Pallempati, G.; Rai, A.; Singh, A. Evaluation of antidepressant activity of vanillin in mice. Indian J. Pharmacol. 2013, 45, 141–144. [PubMed] 76. Lakusi´c,B.; Lakusi´c,D.; Risti´c,M.; Marceti´c,M.; Slavkovska, V. Seasonal variations in the composition of the essential oils of Lavandula angustifolia (Lamiacae). Nat. Prod. Commun. 2014, 9, 859–862. [PubMed] 77. Liu, C.S.; Adibfar, A.; Herrmann, N.; Gallagher, D.; Lanctôt, K.L. Evidence for inflammation-associated depression. Curr. Top. Behav. Neurosci. 2017, 31, 3–30. [PubMed] 78. De Moura, J.C.; Noroes, M.M.; Rachetti, V.P.S.; Soares, B.L.; Delia, P.; Nassini, R.; Materazzi, S.; Marone, I.M.; Minocci, D.; Geppetti, P.; et al. The blockade of transient receptor potential ankirin 1 (TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice. Br. J. Pharmacol. 2014, 171, 4289–4299. [CrossRef] [PubMed] 79. Riella, K.R.; Marinho, R.R.; Santos, J.S.; Pereira-Filho, R.N.; Cardoso, J.C.; Albuquerque-Junior, R.L.; Thomazzi, S.M. Anti-inflammatory and cicatrizing activities of thymol, a monoterpene of the essential oil from Lippia gracilis, in rodents. J. Ethnopharmacol. 2012, 143, 656–663. [CrossRef][PubMed] 80. Hasan, S.K.; Sultana, S. Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats. Toxicol. Mech. Methods 2015, 25, 559–573. [PubMed] 81. Koivisto, A.; Chapman, H.; Jalava, N.; Korjamo, T.; Saarnilehto, M.; Lindstedt, K.; Pertovaara, A. TRPA1: A transducer and amplifier of pain and inflammation. Basic Clin. Pharmacol. Toxicol. 2014, 114, 50–55. [CrossRef][PubMed]

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).