The monoamine oxidase inhibitory activity of essential oils obtained from Eryngium species and their chemical composition.
Context Monoamine oxidase (MAO) inhibitors are used in the treatment of depression, anxiety disorders, and the symptomatic treatment of Parkinson's disease. Eryngium, the most representative of the Apiaceae family, is well known for the presence of essential oils (EOs), which have already demonstrated MAO inhibitory potential. Objective The objective of this study is to evaluate the MAO inhibitory capacity of the EOs obtained from Eryngium floribundum Cham. & Schlecht. (EF), E. eriophorum Cham. & Schlecht. (EE), E. nudicaule Lam. (EN), E. horridum Malme (EH), and E. pandanifolium Cham. & Schlecht. (EP). Materials and methods EOs were obtained from fresh whole plants by hydrodistillation (3 h). Chemical analyses were performed by GC/MS using apolar and polar columns, with oven temperature from 60 to 300 °C at 3 °C/min. The MAO-A and -B activities were evaluated in vitro by an end-point method using kynuramine as the substrate and mitochondrial suspension or human recombinant enzymes as the enzymatic source. DMSO 2%, clorgyline 10−7 M, and pargyline 10−6 M were used as controls. Results and discussion EFEO, EEEO, ENEO, EHEO, and EPEO GC/MS analysis showed (E)-caryophyllene (4.9–10.8%), germacrene D (0.6–35.1%), bicyclogermacrene (10.4–17.2), spathulenol (0.4–36.0%), and globulol (1.4–18.6%) as main constituents. None of the EOs inhibited MAO-A activity (4 and 40 μg/mL). However, EHEO inhibited MAO-B activity with an IC50 value of 5.65 μg/mL (1–200 μg/mL). Pentadecane (10 μM), its major constituent (53.5%), did not display significant MAO-B inhibition. Conclusion The study demonstrates the promising application of Eryngium species as a source of potential central nervous system bioactive secondary metabolites, specially related to neurodegenerative disorders.
Keywords: Neurodegeneration; Parkinson's disease; pentadecane
Introduction
Monoamine oxidase (MAO; EC1.4.3.4) is an enzyme responsible for the oxidative deamination of monoamines, involved with many mental disorders and behavioural effects of some psychotropic drugs. MAO exists in two isoforms: A and B. MAO-A is inhibited by clorgyline and is responsible for the oxidation of serotonin, while MAO-B is inhibited by l-deprenyl; benzylamine and 2-phenylethylamine are substrates. Both isoforms are able to oxidize dopamine, noradreanline, adrenaline, tryptamine, and tyramine. Taking into account their substrates, MAO have been focus of extensive studies in the development of new and effective inhibitors. Inhibition of MAO-A is related to antidepressant effect, while MAO-B inhibitors are associated with the treatment of Parkinson's disease. However, it is well known that MAO inhibitors are responsible for a series of adverse effects, as liver toxicity and hypertensive crises (Youdim & Bakhle [29]; Youdim et al. [30]).
Traditionally, plants are an important source of psychoactive substances. As demonstrated by Adams et al. ([1]), several plant families are able to demonstrate central nervous system (CNS) effects, such as Lamiaceae, Polygalaceae, and Apiaceae. Eryngium L. is the largest genus in the Apiaceae family, accounting for about 75% of species diversity of the subfamily Saniculoideae. It comprises approximately 250 species distributed in temperate regions of every continent. There are four known centres of diversity in the world, including western Mediterranean, southwest Asia, central-west Mexico, and central-east South America (Calviño et al. [4]). In fact, there are more than 100 species distributed in the western hemisphere, mainly concentrated in southern Brazil, Paraguay, Uruguay, and northern Argentina (Mathias et al. [15]).
There are several pharmacological activities described for the genus. Küpeli et al. ([12]) demonstrated the anti-inflammatory activity of ethanolic and aqueous extracts obtained from the aerial parts and roots of eight Turkish Eryngium species. It was observed that E. maritimum L. and E. kotschyi Boiss. possess the most promising results, also exhibiting antinociceptive effect. The antimutagenic capacity of the ethanolic extract of E. creticum Lam. was also described, inhibiting the mutagenicity induced by N-methyl-N′-nitro-N-nitrosoguanidine, mainly attributed to an increased recovery at the chromosomal level (Khader et al. [11]). Beside the activity of the extracts of Eryngium species, Cavaleiro et al. ([5]) also demonstrated the antifungal effect of the essential oil of E. duriaei subsp. juresianum (Laínz) Laínz, with MIC values ranging from 0.16 to 0.32 μL/mL against several dermatophyte species. Indeed, Eryngium species are known for the essential oil production (Palá-Paúl et al. [18]; Flamini et al. [8]; Thiem et al. [27]).
Considering that essential oil constituents had already demonstrated the capacity to inhibit MAO (Tao et al. [26]), this study aims to assess the MAO inhibitory effect of the essential oils obtained from South-Brazilian Eryngium species, namely E. floribundum Cham. & Schlecht., E. eriophorum Cham. & Schlecht., E. nudicaule Lam., E. horridum Malme and E. pandanifolium Cham. & Schlecht., as well as to chemically characterize these essential oils.
Materials and methods
Chemicals
Kynuramine dihydrobromide, pargyline hydrochloride, clorgyline hydrochloride, pentadecane, and DMSO were purchased from Sigma Chemical Co. (St. Louis, MO). Human MAO-A and MAO-B Supersomes TM were acquired from BD Gentest (Woburn, MA). Diethyl ether was acquired from Tedia Company, Inc. (Fairfield, OH). All remaining chemicals used were of analytical grade and were purchased from Sigma-Aldrich (Darmstadt, Germany).
Plant material
Eryngium floribundum, E. horridum, and E. pandanifolium were collected from Guaíba, Rio Grande do Sul, Brazil, in April 2012. Eryngium eriophorum and E. nudicaule were collected from Santo Antônio da Patrulha, Rio Grande do Sul, Brazil, in July 2012. The species were identified by Dr. Sérgio Augusto de Loreto Bordignon and vouchers were deposited at the herbarium of the Departmento de Botânica of the Universidade Federal do Rio Grande do Sul under the numbers ICN 190623, 190628, 190627, 190631, and 190632, respectively.
Essential oil extraction
Fresh materials were reduced and submitted to hydrodistillation in a Clevenger-type apparatus for 3 h. The oils were collected and the sample yields were based on dry weight. All the samples were stored at 4 °C in the dark. Before the analysis, the oils were diluted with diethyl ether.
Analysis by GC-MS
The GC-MS was carried out on a Shimadzu mass spectrometer (GC/MS-QP5000, Shimadzu Corp, Tokyo, Japan) connected with cylindric quadrupole and operated at 70 eV ionization energy. An apolar Durabond-DB5 column (Agilent Technologies, Inc., Atlanta, GA) (30 m × 0.25 mm × 0.25 μm) was used. To confirm, a polar column was also used (LM-120). The temperature was programmed from 60 to 300 °C at 3 °C/min and the injector and detector temperatures were set at 220 °C and 250 °C, respectively. CG-FID was used for quantification (Limberger et al. [13]; Simões-Pires et al. [24]). The relative composition of the oils was obtained by electronic integration and the identification of the compounds was based on the comparison with retention indices, determined relatively to the retention times of a homologous series of n-alkanes, and mass spectra of commercial database (NIST) and literature (Adams [2]).
MAO inhibitory assay
MAO inhibitory assay was performed with two different sources of enzyme. First, essential oils were evaluated using a mitochondrial suspension as source of MAO. Later, the IC50 value of the most active oil and the pentadecane activity was obtained using human recombinant MAO-A or MAO-B. Both assays were carried out in black polystyrene 96-well microtiter plates in a final volume of 200 μL. For the first method, 140 μL of PBS (pH 7.4), 10 μL of pargyline 10 μM (for MAO-A) or clorgyline 10 μM (for MAO-B), 20 μL of kynuramine 0.5 mM, and 10 μL of the samples (in DMSO) were preincubated for 20 min at 37 °C. 20 μL of the mitochondrial suspension 0.5 mg/mL (obtained as described by Passos et al. [22]) was added and the plate was incubated for 30 min at the same temperature. Finally, 75 μL of NaOH 1M was used to stop the reaction. DMSO 2%, clorgyline 10−7 M (MAO-A inhibitor), pargyline 10−6 M (MAO-B inhibitor), and both clorgyline and pargyline (as 100% of inhibition) were used as controls. In the second method, the plate was preincubated as described above, however with 158 μL of potassium phosphate buffer pH 7.4, 2 μL of the sample diluted with DMSO and 20 μL of kynuramine 0.5 mM. Later, it was added 20 μL of the enzyme (MAO-A 0.09 mg mL−1 or MAO-B 0.15 mg mL−1) and, after the incubation (30 min at 37 °C), 25 μL of NaOH 1 M was used to stop the reaction. DMSO 1% and clorgyline 10−6 M (100% of inhibition) and 10−8 M (50% of inhibition) for MAO-A, or pargyline 10−5 M (100% of inhibition) and 10−7 M (50% of inhibition) for MAO-B were used as controls. The fluorescence of both experiments were measured on a Wallac EnVision high-throughput screening microplate reader (PerkinElmer Life and Analytical Sciences, Turku, Finland), at an excitation wavelength λ = 310 nm and an emission wavelength λ = 400 nm. The oils were first tested at the concentrations of 4 and 40 μg mL−1 and, to obtain the IC50 value the doses were ranged from 1 to 200 μg/mL. Pentadecane was evaluated at the doses of 1 and 10 μM.
Statistical analysis
Data analysis was performed using Prism 5.0 (GraphPad Software, Inc., San Diego, CA) and the IC50 value was calculated by adjusting the experimental data (% of inhibition versus concentration) to non-linear regression curves.
Results and discussion
GC-MS analysis
None of the Eryngium species are known for containing large amounts of oil, as pointed out by Palá-Paúl et al. ([20]). In the present study, the yields obtained for Eryngium species were about 0.1%, corroborating with the results previously reported.
All the compounds identified for the essential oils, retention indices and their relative percentages are presented in Table 1. The main components observed were (E)-caryophyllene, germacrene D, bicyclogermacrene, spathulenol, and globulol. Germacrene D and bicyclogermacrene have already been extensively described as main constituents for other species of the genus, such as E. rosulatum P.W. Michael (Palá-Paúl et al. [19]), E. amethystinum L. (Flamini et al. [8]), and E. bourgatii Gouan (Palá-Paúl et al. [21]). However, the detection of pentadecane as the main constituent of E. horridum is very atypical. In fact, the presence of aliphatic components in essential oils of Eryngium species is not common and, if they occur, it is usually in low concentrations.
Table 1. Chemical composition of the essential oils obtained from Eryngium floribundum (EF), Eryngium eriophorum (EE), Eryngium nudicaule (EN), Eryngium horridum (EH), and Eryngium pandanifolium (EP).
| Compound | RIa | EF% | EE% | EN% | EH% | EP% |
| α-Pinene | 927 | – | t | – | – | – |
| β-Pinene | 970 | – | t | – | – | – |
| Limonene | 1024 | – | t | – | – | – |
| cis-Chrysanthenyl acetate | 1255 | 6.0 | – | – | – | – |
| Bornyl acetate | 1278 | – | – | – | – | t |
| n-Tridecane | 1294 | – | – | – | t | – |
| α-Terpinyl acetate | 1341 | – | – | – | t | – |
| 2,3,6-Trimethyl benzaldehyde | 1351 | 15.7 | – | – | – | – |
| α-Copaene | 1364 | – | t | t | – | t |
| β-Bourbonene | 1373 | 0.8 | – | – | – | – |
| β-Elemene | 1381 | 3.3 | 5.4 | 0.9 | – | 4.0 |
| n-Tetradecane | 1390 | – | – | – | t | – |
| 2-epi-β-Funebrene | 1399 | – | – | 0.1 | – | 1.4 |
| β-Funebrene | 1400 | 2.9 | – | – | – | |
| (E)-Caryophyllene | 1406 | 4.9 | 7.1 | 10.8 | – | 5.2 |
| β-Copaene | 1415 | 0.1 | – | – | – | t |
| α-Cedrene | 1416 | – | – | – | t | – |
| cis-Thujopsene | 1417 | – | 1.2 | – | – | – |
| α-trans–Bergamotene | 1424 | – | – | t | – | – |
| Aromadendrene | 1424 | 0.2 | – | – | 9.1 | – |
| (Z)-β-Farnesene | 1432 | – | – | t | – | – |
| α-Humulene | 1439 | 0.4 | 2.7 | 4.7 | – | 0.3 |
| allo-Aromadendrene | 1446 | – | – | – | 1.6 | – |
| (E)-β-Farnesene | 1447 | t | – | 1.6 | – | – |
| Dauca-5,8–diene | 1457 | – | – | t | – | – |
| β-Acoradiene | 1460 | t | – | – | – | – |
| γ-Decalactone | 1460 | – | – | – | 7.4 | – |
| 10-epi-β-Acoradiene | 1462 | – | – | 5.6 | – | – |
| γ-Muurolene | 1465 | t | – | 1.8 | – | – |
| Germacrene D | 1469 | 0.6 | 35.1 | 5.4 | – | 28.9 |
| β-Selinene | 1473 | – | 1.8 | – | – | 3.3 |
| Viridiflorene | 1481 | t | – | – | – | – |
| Bicyclogermacrene | 1486 | – | 10.4 | 17.2 | – | 12.8 |
| α-Muurolene | 1487 | – | – | – | – | t |
| trans-β-Guaiene | 1489 | – | – | 5.0 | – | – |
| Cuparene | 1490 | t | – | – | – | – |
| Pentadecane | 1490 | – | – | – | 53.5 | – |
| Germacrene A | 1492 | – | 3.8 | 1.0 | – | 2.2 |
| β-Bisabolene | 1496 | 0.2 | 2.9 | 7.5 | – | – |
| (Z)-γ-Bisabolene | 1503 | – | – | 1.4 | – | – |
| γ-Amorphene | 1509 | – | 1.3 | – | – | – |
| δ-Cadinene | 1511 | – | – | 1.3 | – | 3.0 |
| Dauca-4(11),8-diene | 1514 | – | t | – | – | – |
| Silphiperfol-5-en-3-one B | 1535 | – | 0.8 | – | – | – |
| epi-Longipinanol | 1538 | t | – | – | – | – |
| Germacrene B | 1543 | – | t | – | – | 4.4 |
| (E)-Nerolidol | 1554 | – | t | 0.1 | – | t |
| Longipinanol | 1567 | – | – | 4.6 | – | – |
| Spathulenol | 1568 | 36.0 | 6.2 | – | 0.4 | 6.4 |
| Caryophyllene oxide | 1570 | – | 3.3 | – | – | 4.3 |
| Globulol | 1576 | 7.0 | 1.4 | – | 18.6 | 1.8 |
| Salvial-4(14)-en-1-one | 1581 | – | 1.5 | – | – | 2.0 |
| Viridiflorol | 1582 | 5.0 | – | 0.3 | 4.6 | – |
| Cedrol | 1590 | – | – | 1.2 | – | – |
| Rosifoliol | 1592 | 2.7 | – | – | t | – |
| Guaiol | 1595 | – | – | t | – | – |
| Khusimone | 1596 | t | – | – | – | – |
| Humulene epoxide II | 1597 | – | – | t | – | – |
| Junenol | 1605 | – | – | – | – | t |
| cis-Cadin-4-en-7-ol | 1621 | – | – | – | – | t |
| allo-Aromadendrene epoxide | 1625 | – | t | – | – | t |
| 3-iso-Thujopsanone | 1637 | – | 1.2 | – | – | – |
| Cubenol | 1637 | – | – | – | – | t |
| α-Muurolol | 1638 | – | – | t | – | t |
| α-Cadinol | 1645 | 4.9 | 4.9 | – | – | 11.1 |
| γ-Dodecalactone | 1668 | 1.8 | – | – | – | – |
| Khusinol | 1670 | – | – | – | – | t |
| α-Bisabolol | 1675 | 0.1 | 2.9 | – | – | 1.0 |
| Germacra-4(15),5,10(14)-trien-1-α-ol | 1677 | t | – | – | – | – |
| Eudesma-4(15),7-dien-1-β-ol | 1678 | – | t | 0.9 | – | – |
| (E)-Nerolidol acetate | 1692 | – | – | t | – | – |
| Mint sulfit | 1723 | – | – | 1.4 | – | – |
| Isobicyclogermacrenal | 1724 | t | 0.2 | 1.8 | – | – |
| Cyclocolorenone | 1730 | – | – | 14.7 | – | – |
| α-Sinesal | 1743 | – | – | 1.4 | – | – |
| Hexadecanal | 1803 | – | – | – | t | – |
| Total | | 92.5 | 94.1 | 90.7 | 95.2 | 92.1 |
1 aRelative retention index experimentally determined against n-alkanes on Durabond-DB5 column; t = trace.
It is also worth mentioning the great difference between the constituents of the oils. Actually, none of the compounds is common for all the essential oils. This great variability in the metabolic constitution of the oils had already been suggested by other authors (Flamini et al. [8]). Palá-Paúl et al. ([20],[21]) verified that phyllocladene and derivatives are the principal components for E. bourgatii and E. glaciale Boiss., which grow under the same climatic conditions. However, 2,4,5- and 2,4,6-trimethylbenzaldehyde are detected in low quantities in these species and are present as the main components for E. foetidum L., E. maritimum, E. yuccifolium Michx., and other species. As suggested by the authors, many factors, such as geographical origin, climatic conditions, and others, may affect the metabolic constitution of essential oils of Eryngium species.
MAO inhibition
Tao et al. ([26]) demonstrated that volatile oil constituents, as eugenol, have the capacity to inhibit monoamine oxidase in vitro. Taking this into account, in the present study, we aimed to evaluate the MAO inhibitory capacity of the essential oils obtained from Eryngium species.
First, we performed a screening with all essential oils, using two different concentrations (4 and 40 μg mL−1). The results are represented in Figure 1. It was observed that none of the essential oil was able to significantly inhibit rat MAO-A activity. However, with respect to the effect on rat MAO-B, the oil of E. pandanifolium inhibited the enzyme in the order of 26 ± 4% (4 μg/mL) and 41 ± 4% (40 μg/mL), while the oil of E. horridum was able to inhibit in the order of 31 ± 7% and 79 ± 1%, for 4 and 40 μg/mL. The variability observed for the pharmacological results may be a reflex of the chemical differences.
Graph: Figure 1. Inhibitory effect (%) of Eryngium floribundum (EF), Eryngium eriophorum (EE), Eryngium nudicaule (EN), Eryngium horridum (EH), and Eryngium pandanifolium (EP) on monoamine oxidase B activity. The samples were evaluated at 40 and 4 μg mL−1. Error bars represent standard deviation (n = 3).
Considering that the essential oil of E. horridum demonstrated a high potency against MAO-B, the IC50 value was determined using human recombinant enzyme (BD Gentest). Using concentrations varying from 1 to 200 μg/mL, the IC50 value was calculated as 5.65 μg/mL. The maximum inhibition obtained for the tested oil was 94% (at the dose of 200 μg mL−1) and the Hill coefficient in the concentration–response equation was 1.022, indicating an ideal behaviour (Copeland [6]).
The MAO-B inhibitors are mainly related to the potential application as antiparkinson drugs. In fact, people with Parkinson's disease possess higher levels of MAO-B as a consequence of gliosis, promoting a malfunction in the dopaminergic system (Youdim et al. [30]). Moreover, the loss of dopaminergic neurons in substantia nigra accompanied by the presence of Lewy bodies has also been detected (Jenner [10]). MAO-B inhibitors have been described as a good option for the early treatment of the disease, promoting a mild effect on motor symptoms, also delaying the use of levodopa (Löhle & Reichmann [14]). In addition, MAO-B selective inhibitors are not associated with the 'cheese effect', which is common for non-specific MAO inhibitors (Finberg & Gillman [7]).
It is well known that oxygen heterocyclic compounds are usually able to inhibit MAO-B activity, as coumarins, chromones, and chalcones (Helguera et al. [9]). However, taking into account the GC/MS data obtained for E. horridum essential oil, the main compound is pentadecane (53.5%), which is an aliphatic carbon chain. As far as we know, there is no report describing the interaction between a carbon chain and the active site of MAO-B. For this reason, a different mechanism of action has been proposed.
The MAO-B (BD SupersomesTM, BD Biosciences, San Jose, CA) consists of microsomes prepared from insect cells infected with a virus engineered to express the enzyme. Thus, it is not just the enzyme, but membrane constituents are also present during the experiment of MAO inhibition. As highlighted by Novaroli et al. ([17]), MAO-B is a membrane-bound enzyme and the mitochondrial microenvironment is important for enzyme activity. In fact, the membrane seems to have a role in increasing the local substrate concentration at the active site of MAO-B (Binda et al. [3]).
There are several reports demonstrating the interaction between n-alkanes, like pentadecane, with lipid bilayers membranes. Pope & Dubro ([23]) observed that in low concentrations, the alkanes may be dissolved between the lipid chains, without great changes in the bilayer structure. However, longer chains in higher concentrations may align parallel to the lipid acyl chains, increasing the bilayer width and affecting the hydrocarbon chain packing and chain tilt (McIntosh et al. [16]). Considering that pentadecane, the main constituent of the oil of E. horridum, is a long-chain hydrocarbon, it is possible that this compound interacts with the bilayer membrane, promoting some conformational changes in it. This interaction may lead to disturbs in some membrane functions, modifying the arrangement around MAO-B, resulting in modified enzyme activity (Szögyi & Cserháti [25]).
In order to evaluate the role of pentadecane in the inhibitory effect of the essential oil of E. horridum, the n-alkane was evaluated in the enzymatic assay. It was observed that, neither in the higher doses tested (10 μM) the compound was able to inhibit MAO-B activity. Taking this result into account, it is proposed that pendadecane is just responsible for modifying some physicochemical parameters of MAO-B, may be facilitating the entrance of other constituents into the active site, however without the capacity to directly inhibit the enzyme activity. Moreover, as already discussed by Williamson ([28]), synergy is very common to occur in essential oils, and other compounds may be responsible for the activity of E. horridum.
Conclusions
As far as we know, this is the first time that the chemical constitution of the essential oils from South-Brazilian Eryngium species is described. Moreover, through the pharmacological evaluation of the oils, no significant effect was detected over MAO-A. On the contrary, E. horridum essential oil was able to inhibit MAO-B activity in the order of 94% (at the dose of 200 μg/mL), demonstrating the promising application of Eryngium species as a source of potential CNS bioactive secondary metabolites.
Declaration of interest
The authors report that they have no conflicts of interest. L. C. K. -J., C. S. P., J. S., and A. T. H. acknowledge the fellowship from CNPq/Brazil. T. J. T. S. thanks for the fellowship from CAPES/Brazil and F. G. B. is recipient of a fellowship from FAPERGS/Brazil. The work was supported by CNPq.
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By Luiz Carlos Klein-Júnior; Carolina dos Santos Passos; Tiago Juliano Tasso de Souza; Fernanda Gobbi de Bitencourt; Juliana Salton; Sérgio Augusto de Loreto Bordignon and Amélia Teresinha Henriques
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