Sideritis in mood disorders and adhd

Extracts of Sideritis scardica as inhibitors of monoamine transporters:
A pharmacological mechanism for efficacy in mood disorders and attention-deficit
hyperactivity disorder (ADHD)
Aim of the study: Sideritis species are traditionally used within the mediterranean area for the cure of cold cough
and for the treatment of gastrointestinal disorders. The aim of this study was to investigate the effects of Sideritis
extracts on the monoamine transporters and to derive possible medicinal applications from the
pharmacological profile of the extracts.
Methods: We have studied the effect of various Sideritis scardica extracts on serotonin, noradrenaline and
dopamine uptake into rat brain synaptosomes and serotonin uptake into human JAR cells.
Results: All extracts inhibited the uptake of all three monoamines into rat brain synaptosomes by their respective
transporters, the alcoholic extracts being more effective than the water extract. EC50 values were in the range of
30-40 µg/ml. Inhibition of the human serotonin transporter by the methanol extract was even more effective
(EC50: 1,4 µg/ml). Combining Sideritis ethanol extract and fluvoxamine resulted in a leftward shift of the
fluvoxamine concentration-response curve.
Conclusions: The pharmacological profile of Sideritis scardica extracts suggests their use in the phytochemical
therapy of mental disorders associated with a malfunctioning monoaminergic neurotransmission, like major
depression or the attention-deficit hyperactivity disorder.
1. Introduction
The chemical constituents of Sideritis have been investigated for a long time. The essential oil of all The genus Sideritis (Lamiaceae) comprises about Sideritis species mainly consists of α-pinene, β- 150 species distributed mainly in the mediterranean pinene, β-caryophyllene, caryophyllene oxide, area and in the moderate zones of Asia. The taxa are attributed to three sections: sect. Sideritis, sect. germacrene D, spathulenol, α-bisabolol, fenchone Empedoclia (Rafin.) Bentham. and sect. Hesiodora and sabinene (10,11). The main components vary Bentham. They are growing in low-fertility hilly between the species. In addition, 8-hydroxyflavone and mountainous areas at over 800-1000 m altitude allosylglucosides and p-coumaroylglucosides are found in several Sideritis species (12). For some species the presence of phenylpropanoid glycosides Plants of the genus Sideritis are widely used in folk (3) or kaurane diterpenoids (13,14) is reported. medicine in the eastern mediterranean area for the cure of cold cough and for the treatment of (ent-6α-8α-18-trihydroxy-13(16),14- gastrointestinal disorders. This is due to their anti- labdadiene), a diterpene found in Sideritis foetens, inflammatory (3,4), antibacterial and antifungal has been shown to inhibit iNOS expression in (5,6) activities. Studies on the pharmacological macrophages. It is supposed that this effect is action of Sideritis revealed diuretic (7), antioxidant caused by a transcriptional mechanism. This inhibition of iNOS by andalusol and related substances might be responsible for the anti- Sideritis has become very fashionable in Germany inflammatory effect of Sideritis species, since iNOS recently and is found in a variety of shops marketed is the enzyme responsible for the high-output NO as “Bergtee” or “Griechischer Bergtee”. The herb is sold cut or sometimes even whole, the latter making identification much easier. The majority of species An imbalance in monoaminergic neurotransmission sold in Germany consists of Sideritis syriaca, is considered to be responsible for a multitude of Sideritis dichotoma and Sideritis scardica. The mood disorders. Mood disorders and conditions of important role of the leaves and flowering tops of impaired or diminished cognition and attention Sideritis as traditional tea in the eastern affect more than one in every four persons in the mediterranean area and Spain (mountain tea, developed world. Representative examples include malotira, dag cay, té de puerto) has imposed the depressive disorders, generalised anxiety disorders need of cultivation of Sideritis since the production or the attention-deficit hyperactivity disorder. In the from wild-collected plants was insufficient to cover central nervous system, dopamine is involved in controlling locomotion, cognition, affect and mood, noradrenaline is involved in modulating attention, working memory, behavioural inhibition, planning, PSA07080901). The raw plant material was alertness, arousal, mood and vigilance. Serotonin plays a role in mood, aggression, anxiety, appetite, laboratory. Voucher specimens of the crude sleep, cognition, learning and locomotion. botanicals are deposited at the trader’s facilities. The dry herb was ground and extracts were Most antidepressants increase synaptic levels of the prepared by boiling the plant material for 1 h under monoamine neurotransmitter serotonin. They may reflux with the respective solvent (water, methanol, 70% ethanol). The extracts were filtered and dried neurotransmitters, noradrenaline and dopamine. by rotary evaporation. Yields of the extract was This observation gave rise to the monoamine 320-340 mg (water extract), 100-120 mg per g plant hypothesis of depression. In its contemporary material (methanol extract) and 200-240 mg extract formulation, the monoamine hypothesis postulates per g plant material (70% ethanol extract). that the deficit of certain neurotransmitters is responsible for the corresponding features of depression. There are several different monoamine 2.2
Monoamine uptake experiments
transporters: the dopamine transporter DAT, the 2.2.1
Rat brain synaptosome experiments
noradrenaline transporter NET and the serotonin transporter SERT. Modern antidepressants typically Male Wistar rats (250-300 g) were decapitated work by binding to the corresponding transporter under CO2 anaesthesia and the brain was quickly and thereby inhibiting serotonin, noradrenaline or removed. Cortex was prepared on ice. The cortical dopamine reuptake and raising active levels in the tissue was homogenised in 10 volumes ice cold homogenate was centrifuged for 10 min at 4° C and Attention-deficit hyperactivity disorder (ADHD) is 900*g. The supernatant was centrifuged again for a heterogeneous behavioural disorder characterised 10 min at 4° C and 11000*g. The supernatant was by inattention or lack of focus, hyperactivity and discarded and the pellet was kept on ice. At the impulsivity. Recent genetic and neuroimaging beginning of the experiment, the pellet was studies provide evidence for contributions of a resuspended in buffer to yield a suspension with a dopaminergic and noradrenergic systems suggests The uptake experiments were performed in 96 well that normalizing their activities in relevant brain filter plates (GF-C glass fiber filter Multiscreen FB, areas is necessary for the treatment of ADHD (17). Millipore, Schwalbach, Germany). Each well was washed with 250 µl of buffer containing 121 mM Especially in the case of central nervous system disorders, a large majority of the patients would prefer nature medicine (18). Example of plants with mM glucose, 0.57 mM ascorbic acid, saturated with central nervous action are Valeriana officinalis 95% O2/5% CO2, final pH 7.4. 50 µM pargyline (valerian) and Humulus lupulus (hops), both used were added for the inhibition of MAO. 50 µl for sleep disturbances, or Passiflora incarnata synaptosome preparation in buffer was added to (passion fruit) and Hypericum perforatum (St. John’s wort) used for the treatment of affective concentrations of extracts dissolved in DMSO (final concentration of DMSO 10 µl/well, 8 wells per extract concentration) in a total volume of 240 µl Although Hypericum extracts are well established for 10 min. After addition of 10 µl of a 100 nM in the phytotherapy of depression, it would be serotonin solution in buffer containing 0.1 µCi of desirable to have other phytopharmaceutical entities [³H]-serotonin the plates were incubated for 10 min with a proof of action for the therapy of central at room temperature, the uptake buffer was then nervous disorders caused by an imbalance in rapidly filtered off, and the filter was washed three monoamine neurotransmission. The aim of this times with 250 µl buffer. The filters were punched study was to investigate the effects of Sideritis out and transferred into scintillation vials for liquid scardica extracts on the monoamine transporters scintillation counting. Nonspecific uptake was and to derive possible medicinal applications from defined as uptake in the presence of 10 µM the pharmacological profile of the extracts. Noradrenaline and dopamine uptake experiments 2. Materials and methods
were performed as described above. The final 2.1
Plant extracts
concentrations of radiolabelled transmitter were 20 Farm-cultivated aerial parts of Sideritis scardica dopamine). The plates were incubated for 15 min at 37° C. Unspecific binding was determined in the Meckenheim, Germany (Product No.: 1127, Lot: 2.2.2
Uptake experiments using JAR cells
curve fitting routines (SigmaPlot® 8.0, SPSS Science, Chicago, Illinois, USA). The errors given In addition, serotonin uptake experiments were in this paper represent standard error of mean performed with human placental choriocarcinoma cells (JAR) which constitutively express the human 3. Results
JAR cells (DSMZ, Braunschweig, Germany) were 3.1
Rat brain synaptosomes
glutamine, 10% foetal calf serum, 100 U/ml Concentration-response curves were recorded for penicillin, and 100 mg/ml streptomycin at 37° C in the inhibition of the monoamine transporters. The an atmosphere of 5% CO2, 95% air. The uptake methanol extract of Sideritis scardica inhibited the experiments were performed in poly-(D-lysine)- uptake of [³H]-serotonin, [³H]-noradrenaline and coated 24-well plates (1 day after plating; 50000 - [³H]-dopamine into rat brain synaptosomes with 200000 cells/well). Each well was washed twice EC50 values of 31.0 µg/ml [16.4; 58.6] for serotonin with 1 ml of buffer containing 10 mM HEPES, 120 uptake, 42.3 µg/ml [31.8; 56.4] for noradrenaline mM NaCl, 3 mM KCl, 2 mM CaCl2, 2 mM MgCl2, uptake and 37.0 µg/ml [27.5; 49.8] for dopamine 5 mM glucose and 0.57 mM ascorbic acid final pH uptake (Figure 1). Maximum inhibition was 108% 7.3 and incubated with various concentrations of ± 6% for serotonin, 90% ± 6% for noradrenaline extracts dissolved in DMSO (final concentration of DMSO 10 µl/well, 4 wells per concentration) in a total volume of 1 ml. After addition of 10 µl of a The water extract of Sideritis scardica also 100 nM serotonin solution in buffer containing 0.1 inhibited the uptake of the monoamines with µCi of [³H]-serotonin the plates were incubated for similar EC50 values but mostly lower maximum 10 min at room temperature, the uptake buffer was effects. EC50 values were 38.5 µg/ml [20.4; 72.8] then rapidly aspirated, and the cells were washed for serotonin uptake, 30.6 [25.1; 37.5] for three times with 1 ml buffer. Cells were lysed with noradrenaline uptake and 45.5 [31.4; 66.0] for 0.5 ml of 0.5 M NaOH and transferred into dopamine uptake. Maximum inhibition was 70% ± scintillation vials for liquid scintillation counting. 8% for serotonin, 122 % ± 13% for noradrenaline Nonspecific uptake was defined as uptake in the 3.2
JAR cells (human serotonin transporter
Effect of Sideritis scardica extracts on
cell viability
Inhibition of hSERT by Sideritis scardica
The effect of Sideritis scardica extracts on cell extract
viability was investigated by measuring lactate The concentration-response curve for the uptake of serotonin by the human serotonin transporter extracellular space when the cells are damaged. hSERT was recorded in this set of experiments. Sideritis scardica methanol extract inhibited the concentrations of 50 µg/ml and 500 µg/ml. The uptake of [³H]-serotonin into the human JAR cell JAR cells were incubated at 20° C with the extracts line with a EC50 of 1.4 µg/ml [0.6; 3.5] and a in uptake buffer for 3 h. Assay conditions were maximum inhibition of 70% ± 9%. The 70% adopted from Bergmeyer and Bernt (19). Briefly, ethanol extract showed in this system an EC50 value 100 µl 69 mM sodium pyruvate in 100 mM sodium of 55.9 µg/ml [31.6; 99.3] and a maximum phosphate buffer pH 7.5 were added to 2.8 ml 0,13 mM β-NADH solution in sodium phosphate buffer. 100 µl of JAR cell supernatant (or 100 µl buffer for the control experiments) was added and the change 3.2.2.
Shift of the fluvoxamine dose-response
in absorption at 340 nm was recorded at fixed times curve by Sideritis scardica 70% ethanol extract
We investigated the effect of various concentrations of Sideritis on the inhibition of serotonin uptake by 2.4
fluvoxamine. The concentration-response curve of fluvoxamine (EC50: 3.8 nM [2.2; 6.4]) was shifted Radioactivity accumulated in the filters was to the left by adding Sideritis ethanol extract. normalised as “percent of specific uptake” always Addition of 10 µg/ml Sideritis extract resulted in a referring to the specific uptake obtained from total EC50 for the combination of Sideritis and minus non-specific uptake. EC50 values were fluvoxamine of 1.5 nM [1.2; 1.8], addition of 50 calculated from the normalised data using iterative µg/ml Sideritis extract yielded an EC50 of 0.5 nM with 50 µg/ml and 97% ± 16% with 500 µg/ml Figure 2: Shift of the fluvoxamine concentration-response curve for the uptake of serotonin into human JAR cells in presence of 10 µg/ml and 50 µg/ml Sideritis scardica ethanol extract. Values 4. Discussion
demonstrated that plants of the genus Sideritis have anti-inflammatory (3,4), diuretic (7), antioxidant (8), analgesic (9) and antibacterial and antifungal (5,6) effects. The herbs are traditionally used throughout the mediterranean regions for colds and respiratory problems. They also are used as an anti- inflammatory remedy and to reduce fever. Tea from Sideritis species has become very fashionable in Germany recently, and is to be found in a wide variety of shops. In this study, we have focussed on the commercially available and farm-cultivated species Sideritis scardica, one main constituent of “Bergtee” in Germany and have determined its models for the investigation of monoamine transporter targeting established in our laboratory. The results of the present study illustrate that Figure 1: Concentration-response curves of Sideritis scardica Sideritis scardica is a potent inhibitor of the methanol extract for the uptake of serotonin (A), noradrenaline monoamine transporters. The water and alcoholic (B) and dopamine (C) into rat brain synaptosomes. Values are extracts of Sideritis scardica inhibited the uptake of serotonin, noradrenaline and dopamine by their respective transporters in a concentration-dependent 3.3.
Effect of Sideritis scardica extracts on
manner. The inhibition of the human serotonin cell viability
transporter hSERT (expressed in human JAR cells) by Sideritis scardica methanol extract was even The LDH assay did not show differences between more pronounced than the inhibition of the rat brain controls and cells treated with methanolic Sideritis scardica extract. Relative LDH activities in the supernatant of the JAR cells were 107% ± 14% Combining Sideritis scardica 70% ethanol extract with fluvoxamine leads to a leftward shift of the fluvoxamine concentration-response curve without motivation, pleasure and reward as well as interest in life (21). Increasing any of these three fluvoxamine is needed in the presence of Sideritis neurotransmitters will elevate mood, but the other scardica extract to elicit the same level of elements of depression may be particularly biological response. This increase of drug sensitivity is to be found even at concentrations of neurotransmitter. It is therefore desirable to have a Sideritis, which are per se not active at the remedy which acts on as many monoaminergic serotonin transporter. Sideritis extract increases the concentration-dependent manner more than 8-fold, Extracts of Hypericum perforatum have been used which may be explained by a concerted interaction since antiquity for the treatment of depressive of the two serotonin uptake blockers with the symptoms. The exact mechanisms of action are still serotonin transporter. Other effects than only unclear, nevertheless randomised clinical trials have shown that Hypericum extracts are more effective modulation of the transporter or alteration of the than placebo and similarly effective as standard transporter activity by Sideritis scardica extracts antidepressants while having better tolerability in the acute treatment of major depressive episodes. St John's wort may rarely cause photosensitivity. This The lactate dehydrogenase assay showed that can lead to visual sensitivity to light and to treatment of the JAR cells with Sideritis scardica sunburns in situations that would not normally methanol extract at concentrations up to 500 µg/ml cause them. The most important risk associated did not affect cell viability. This demonstrates that with Hypericum extracts are interactions with other the inhibitory action of the extract on the drugs. St John's wort has also been shown to cause monoamine transporters does not appear to be due multiple drug interactions through induction of the CYP2C9. This results in the increased metabolism In order to exert their mode of action in vivo, the of those drugs, resulting in decreased concentration components of the Sideritis scardica extracts must and clinical effect. Examples of drugs causing be able to cross the blood brain barrier to reach clinically-significant interactions with St John's their target site. Most drugs cross the blood brain wort are antiretrovirals, hormonal contraceptives barrier by transmembrane diffusion. This is a non- saturable mechanism that depends on the melding of the drug into the cell membrane. A high degree A recent study on the Hypericum perforatum of lipid solubility and low molecular weight favour extract Ze 117 showed that it interferes in three crossing by this mechanism. Reviews often quote a ways with the individual uptakes of the monoamine cut-off of 400 to 600 g/mol. Other factors neurotransmitters. EC50 values for this extract were influencing the ability of a drug to partition from 54 µg/ml for noradrenaline uptake, 350 µg/ml for blood into the blood brain barrier include charge, dopamine uptake and 1600 µg/ml for serotonin tertiary structure and degree of protein binding. uptake (23). Therefore, the potency of the Mechanisms for the crossing of the blood brain noradrenaline uptake inhibition was around 30 times higher than that for serotonin, and seven adsorptive endocytosis and the extracellular times higher than that of the dopamine uptake pathways (20). Substances which come into inhibition. Combination of Hypericum perforatum consideration as active elements in the Sideritis with other plant extracts like passion flower of scardica extracts comprise, among others, terpenes, valerian improve the pharmacological profile of the flavonoids and phenols. These substances typically phytodrug by synergistic effects, the EC50 of an show molecular weights in the range of 200 – 400 ethanolic Hypericum extract for serotonin uptake g/mol. They are soluble in alcohol or aqueous into rat brain slices was lowered from 177.5 µg/ml alcohol and therefore are of a lipophilic character. for St. John’s wort extract alone to 37.2 µg/ml in The Sideritis scardica extracts investigated in this the presence of 200 µg/ml of Passiflora extract study are therefore likely to cross the blood brain In contrast to St. John’s wort, Sideritis scardica Depressive disorders are characterised by an extract has EC50 values for all three types of imbalance in monoaminergic neurotransmission. monoamine transporters in the range of 30-40 Based on findings from studies of antidepressants µg/ml. With this background, the pharmacological treatment, it may be possible to assign specific profile of Sideritis scardica extract might be symptoms of depression to specific neurochemical beneficial for the therapy of depressive disorders. It mechanisms. Serotonin may be related to anxiety, elevates the extracellular concentration of all three obsessions and compulsions; noradrenaline to monoamine neurotransmitters by inhibiting their alertness and energy as well as anxiety, attention transporters with similar potency and therefore and interest in life; and dopamine to attention, might ameliorate the symptoms of depression better and more powerful than monospecific drugs. In used to try to help regulate mood and behaviour allopathic pharmacology the debate about the problems associated with ADHD (33). But no one advantage of dual action antidepressants like of these herbal remedies has a proven mechanism venlafaxine and duloxetine is still going on (25,26). of action which would suggest the use of these plant extracts for the treatment of ADHD or even a Another possible application of Sideritis scardica proven efficacy for the treatment of ADHD until extracts as inhibitors of the monoamine transporters consists in the therapy of attention-deficit hyperactivity disorder (ADHD). This behavioural Sideritis scardica extracts inhibit all monoamine disorder is characterised by inattention or lack of transporters with approximately the same potency. With this mode of action, they are the first symptoms have a childhood onset and often persist phytomedical entity with this proven mode of into adolescence and adulthood. Estimates indicate action. All other remedies used in ADHD treatment that 6- 9% of children and adolescents meet show selectivity towards only one of the three diagnostic criteria for ADHD and that the transporters. Methylphenidate has higher affinity to prevalence of ADHD in adults is around 3-5% (27). dopamine transporters than to noradrenaline Genetic data and collective evidence from transporters and very low affinity for serotonin neurobiologic and neuropsychologic studies point transporters. Atomoxetine on the other hand selectively inhibits noradrenaline transport, its catecholaminergic system in ADHD (17). Adequate action at the serotonin transporter is weaker and it catecholaminergic modulation of the prefrontal shows a low affinity towards dopamine transporters cortex, the brain region that plays an important role (28). Sideritis scardica extracts with their ability to in the physiology of cognition and emotion, is inhibit dopamine, noradrenaline and serotonin uptake to the same extent may turn out to be dysfunction of the prefrontal cortex in ADHD has beneficial for a phytochemical therapy of ADHD. been attributed to a decreased catecholamine function affecting cognition and motor inhibition. 5. Conclusions
Since monoamine transporters are (at least in part) Aqueous and alcoholic extracts of Sideritis scardica concentrations of the catecholamines noradrenaline are able to inhibit serotonin, noradrenaline and and dopamine, the common treatment of ADHD dopamine transporters with similar EC50 values. By includes stimulant medications with drugs like inhibiting neurotransmitter reuptake the active methylphenidate. These stimulants block the levels of the monoamines are elevated within the reuptake of noradrenaline and dopamine thus rising synapse. This is a biochemical and pharmacological their extracellular levels. Currently, the only mode of action which suggests to use Sideritis nonstimulant medication approved for the treatment scardica extracts for the treatment of disorders ADHD is atomoxetine, which selectively enhances associated with an altered or malfunctioning extracellular noradrenaline and dopamine levels within the prefrontal cortex (28). Although scardica extracts may be superior to other plant noradrenaline and dopamine are in the main focus extracts in the therapy of depressive disorders, since the long-term traditional use in the mediterranean additional contribution of the serotonergic system area did not reveal side effects of the drug until now. Sideritis scardica extracts also may have a neuroimaging studies provide evidence for separate good potential to get a proof of action as the first contributions of altered dopamine and serotonin plant extract for the treatment of attention-deficit function in this disorder (29). Most tricyclic noradrenaline transporters are good remedies for managing behavioural and, to some extent, Acknowledgements
This study was supported by a grant from the Some parents refuse a therapy of their children with Bundesministerium für Wirtschaft und Technologie stimulants or chemical drugs due to the possible side effects of these drugs. Therefore, a large number of alternative medications of ADHD have been praised. These remedies are often of a References
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