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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 scardica 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 2.3 Effect of Sideritis scardica extracts on hSERT) cell viability 3.2.1 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 Statistics
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 scardicaSideritis 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
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Contact: Dr. Rainer Knörle IBAM GbR Dr. Rainer Knörle & Dr. Peter Schnierle, Ferdinand-Porsche-Strasse 5, D-79211 Denzlingen, Germany,
“But surely sin is a purely abstract concept?” The words from Baxter’s mouth raced across the room at one hundred miles an hour. His hands waved furiously. “Where did sin originate from? From God? Remove God from the equation and you are left with nothing more than a clever way of one set of humans, i. e. the religious sect, controlling another set of humans – the uneducated, weak an
TIPS FOR YOUR GREAT ADVENTURE IN GUANGZHOU (Special thanks to Robin Cayce, Suzie Carter and Betsy Potts for sharing their travel tips) Four Stages of International Travel: 1. Jet lag and wonder.happiness 2. Settling in 3. Depression and homesick 4. Acceptance.home away from home Take it one day at a time, focus on the positive and wait for that home away from h