Author’s Accepted Manuscript

Therapeutic potential of mistletoe in CNS-related

neurological disorders and the chemical
composition of Viscum species

Anna Szurpnicka, Jordan K. Zjawiony, Arkadiusz

Szterk
www.elsevier.com/locate/jep

PII: S0378-8741(18)32801-0
DOI: https://doi.org/10.1016/j.jep.2018.11.025
Reference: JEP11606
To appear in: Journal of Ethnopharmacology
Received date: 2 August 2018
Revised date: 13 November 2018
Accepted date: 15 November 2018
Cite this article as: Anna Szurpnicka, Jordan K. Zjawiony and Arkadiusz Szterk,
Therapeutic potential of mistletoe in CNS-related neurological disorders and the
chemical composition of Viscum species, Journal of Ethnopharmacology,
https://doi.org/10.1016/j.jep.2018.11.025
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 Therapeutic potential of mistletoe in CNS-related neurological disorders and the

chemical composition of Viscum species

Anna Szurpnickaa, Jordan K. Zjawionyb, Arkadiusz Szterkc*

a
Department of Natural Medicinal Products and Dietary Supplements, National Medicines

Institute, Chełmska 30/34, 00-725 Warsaw, Poland,

b
Department of BioMolecular Sciences, Division of Pharmacognosy, Research Institute of

Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS

38677, United States,

c
Department of Spectrometric Methods, National Medicines Institute, Chełmska 30/34, 00-

725 Warsaw, Poland

e-mail: a.szurpnicka@nil.gov.pl

e-mail: jordan@olemiss.edu

e-mail: szterkarkadiusz@gmail.com

*Corresponding author: tel. 22 841 21 21

Abstract

Ethnopharmacological relevance:

Viscum album L., commonly known as mistletoe, has been used for centuries in traditional

medicine to treat various neurological diseases, including epilepsy, hysteria, nervousness,

hysterical psychosis, dizziness and headaches.

Aim of the study:

The aim of this review is to summarize existing evidence confirming the influence of

mistletoe on the central nervous system and to investigate the compounds that may be

responsible for this activity.

Materials and Methods:

1
Available information from studies of various species of the Viscum L. genus was collected

from scientific journals, books, and reports via a library and an electronic data search

(Elsevier, Google Scholar, PubMed, Springer, Science Direct, ResearchGate, and ACS).

Results:

The main chemical constituents of Viscum L. species are viscotoxins, lectins, flavonoids,

phenolic acids, terpenoids, sterols, phenylpropanoids, and alkaloids. Various extracts of

Viscum album L. showed central nervous system activity, including antiepileptic, sedative,

antipsychotic, anxiolytic, antidepressant and antinociceptive effects in mice and rats.

Additionally, the extracts increased the level of brain-derived neurotrophic factor, prevented

apoptotic neuronal death induced by amyloid β and weakly inhibited cholinesterase activity.

Conclusions:

Numerous historical references describe the use of mistletoe for the treatment of central

nervous system disorders. In recent years, studies have started to confirm the antiepileptic,

antipsychotic, sedative and antinociceptive effects of mistletoe. Additionally, mistletoe can be

used as a complementary treatment for Alzheimer’s disease. The therapeutic effect of

mistletoe might be a result of the synergistic interactions of various secondary metabolites,

including mistletoe-specific lectins. Further studies of the chemical composition and CNS

activity of mistletoe are required. The mechanisms of action, target sites, pharmacokinetics,

metabolic mechanisms, adverse effects and interactions of mistletoe with other drugs must

also be investigated, as well.

Graphical abstract

2
Abbreviations

AD, Alzheimer’s disease; APP, amyloidogenic amyloid precursor protein; BACE-1, β-

secretase 1; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; ERK,

extracellular signal-regulated kinase; MAO-A, monoamine oxidase A; MAO-B, monoamine

oxidase B; MAPK, mitogen activated protein kinase; MES, maximum electroshock; MTT, 3-

[4,5- dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide; NMDA, N-methyl-D-aspartate;

NMDLA, N-methyl-DL-aspartic acid; PD, Parkinson’s disease; PI3K/AKT,

phosphatidylinositol 3-kinase; PTZ, pentylenetetrazole; ROS, reactive oxygen species

1. Introduction

For years, plants have been a major sources of new drugs (Harvey, 2008; Newman and Cragg,

2016; Rates, 2001). Many research groups have tried to separate and isolate bioactive

compounds from plants to further study their structure, bioactivity, mechanisms of action and

target sites. The biological activity of a plant is the result of various types and interactions of

3
its secondary metabolites with other important molecules in the organism. This complex

process plays a key role in the defence of plants against herbivores, pathogens and inter-plant

competition. It has been suggested that plant defence against microbial pathogens could prove

useful as antimicrobial medicines in humans. Moreover, plant defence against herbivores via

neurotoxin activity may have beneficial effects in humans, as mediated by their action on the

central nervous system (CNS) (Harvey, 2008; Newman and Cragg, 2016; Rates, 2001).

Additionally, some secondary metabolites have medical activity in humans due to structural

similarities in their potential target sites to those of endogenous metabolites, ligands,

hormones, signal transduction molecules or neurotransmitters. The biological activity of a

plant is also associated with the additive or synergistic action of several metabolites that act at

single or multiple target sites. Moreover, this action may eliminate the side effects associated

with a high-level single synthetic drug in the body (Briskin, 2000). To emphasize the

importance and huge influence of a folk medicine as a medicinal product development, we

point to drugs currently available on the market containing active compounds of natural

origin, including vinblastine and vincristine (Apocynaceae: Catharanthus roseus (L.) G. Don)

which are used in a antitumour therapy (Courdavault et al., 2014), cannabidiol (Cannabaceae:

Cannabis sativa L.) to treat chronic neurophatic pain (Bonini et al., 2018), morphine and

codeine (Papaveraceae: Papaver somniferum L.), which are well-known analgesics,

papaverine (Papaver somniferum L.), which causes the relaxation of the tonus of all smooth

muscle, theophylline (Theaceae: Camellia sinensis (L.) Kuntze), which targets the smooth

muscle of the airways of the lungs (Debnath et al., 2018), and digoxin (Plantaginaceae:

Digitalis lanata Ehrh.), which is used in a treatment of heart diseases (Dec, 2003). It must be

emphasized that modern plant drugs are high-quality pharmaceuticals products manufactured

in accordance with good manufacturing practice (Gurib-Fakim, 2006). European mistletoe

(Santalaceae: Viscum album L.), commonly known as mistletoe, may be a potential source of

4
new drugs for neurological disorders due to its activity in the CNS (Gupta et al., 2012).

Viscum album L. belongs to the family of Santalaceae R. Br. and is native to Europe and

western and southern Asia. Mistletoe is a semi-parasitic evergreen shrub that grows on both

deciduous and coniferous trees. Mistletoe is a branching woody perennial with small leathery

leaves and flowers that ripen into semi-transparent white berries (Bussing, 2000). Mistletoe

has been used for centuries in traditional medicine to treat diseases, including tumours,

inflammation, hypertension, arthritis, rheumatism, constipation, internal haemorrhages,

stomach ulcers, and skin diseases. In ethnopharmacology, mistletoe was also used in the

treatment of CNS disorders such as epilepsy, hysteria, nervousness, nervous spasms,

hysterical psychosis, dizziness and headaches (Bussing, 2000; Committee on Herbal

Medicinal Products, 2012; Lev et al., 2011; Owczarek, 2011). Studies on the

neuropharmacological activity of mistletoe extracts have only recently been published. In

vitro tests show that mistletoe can be a potential drug for the treatment of Alzheimer’s

disease, which is connected with inhibition of amyloid β protein- and hydrogen peroxide-

induces neurotoxicity in cultured rat cortical neurons (Jang et al., 2015; Lee et al., 2007) as

well as low inhibition of cholinesterases (Orhan et al., 2014). Furthermore, in vivo studies

confirmed the neuroprotective and BDNF-stimulating capacity of mistletoe against an

aluminium chloride-induced Alzheimer’s disease model (Ademola et al., 2016; Ekpenyong et

al., 2016). In vivo studies on mice and rats confirmed that mistletoe can be used as a

complementary therapy against epilepsy (Amabeoku et al., 1998; Geetha et al., 2010, 2018;

Gupta et al., 2012; Tsyvunin et al., 2016). Furthermore, other in vivo studies confirmed the

antinocicepative, antidepressant, antistress, antianxiety and antipsychotic activity of mistletoe

on central nervous system (Gupta et al., 2012; Khatun et al., 2016; Kumar et al., 2016; Orhan

et al., 2006). The goal of this review is to summarize scientific data on the potential activity of

mistletoe in relieving and treating CNS disorders, the determination of bioactive compounds

5
responsible for its therapeutic properties and their potential mechanism of action, as well as

future research directions.

2. Chemical constituents and their mechanisms of action

Mistletoe contains bioactive compounds from various chemical classes. Table 1 shows

numerous chemical compounds that have potential therapeutic use that are found in Viscum L.

species. The most unique group includes lectins and viscotoxins. Other compounds isolated

from mistletoe are well known in the plant kingdom. Quantitative and qualitative analyses of

the chemical composition of mistletoe are difficult to perform due to large variability. The

chemical composition of mistletoe is determined by the host plant species (Łuczkiewicz et al.,

2001), the parts of the plant extracted (Vicas et al., 2011), the time of collection (Urech et al.,

2006) and the place of harvest (Zhao et al., 2011). The solvents and methods used for

extraction also affect the final composition (Ko et al., 2016). Furthermore, the results of

quantitative analyses are difficult to compare, due to the use of different analytical techniques

and units used by various authors. The main techniques used include high-performance liquid

chromatography (HPLC) with ultraviolet (UV) detection (Kim et al., 2015; Ko et al., 2016;

Łuczkiewicz et al., 2001; Schaller et al., 1998; Urech et al., 2006) and diode array (DAD)

detection (Vicas et al., 2011; Wójciak-Kosior et al., 2016), gas chromatography-mass

spectrometry (GC-MS) (Ćebović et al., 2008; Orhan and Orhan, 2006; Vlad et al., 2016),

liquid chromatography-mass spectrometry (LC-MS) (Zhao et al., 2011) and liquid

chromatography-tandem mass spectrometry (LC-MS/MS) (Long et al., 2017; Pietrzak et al.,

2017). The resulting units are commonly mg/g of dry extract (Kim et al., 2015; Ko et al.,

2016; Wójciak-Kosior et al., 2016), mg/g of fresh weight of plant (Orrù et al., 1997; Schaller

et al., 1998), and mg/100 g of fresh weight of plant (Lee et al., 2013; Łuczkiewicz et al.,

2001) via the relative proportion method (areas) (Ćebović et al., 2008; Orhan and Orhan,

2006; Vlad et al., 2016).

6
Until now, only a few mistletoe-specific compounds have been tested for

neuropharmacological activity. The mistletoe lectins from Viscum album L. were tested for

their effect on the binding of specific ligands to N-methyl-D-aspartate (NMDA) and sigma

receptors in synaptic plasma membranes from the rat hippocampus. The mistletoe galactose-

specific lectins MLI and MLII (0.01 mg/ml) inhibit the binding of [ 3H]MK-801,

[3H]glutamate, [3H]5,7-DCKA and [3H]glycine to membranes. Mistletoe acetylgalactosamine-

specific lectin MLIII decreases the binding of [3H]SKF 10047. It has been proposed that the

lectin-sensitive ligand binding sites of both the sigma and NMDA receptors are located

separately, and the carbohydrate side chains of the sigma receptor do not participate in the

modulation of the NMDA-receptor (Machaidze and Mikeladze, 2001). It has also been

reported that mistletoe extract that has been standardized for galactoside-specific lectin (ML-

1) increases the beta-endorphin plasma levels in breast cancer patients (Heiny and Beuth,

1994; Heiny et al., 1998). Beta-endorphin is an endogenous opioid that is known for its

antinociceptive effects (Bruehl et al., 2012). Additionally, beta-endorphin may play a role in

stress-related psychiatric disorders and depression (Merenlender-Wagner et al., 2009). The

mechanisms of action of mistletoe lectins on the CNS have not been investigated. However,

many other isolated compounds, which are not unique to Viscum L. species, have been

extensively studied. Based on this knowledge, we assume that similar mechanisms may be

involved in the effects of the same compounds isolated from mistletoe.

The strong effect of mistletoe on the CNS may be due to the presence of flavonoids.

Flavonoids have the ability to cross the blood-brain barrier and reach the CNS, where GABA

is the most important inhibitory neurotransmitter. GABAA receptors are heteromeric GABA-

gated chloride channels. The transmembrane ion channel of GABAA receptors is opened by

stimulation with GABA, which causes an influx of chloride ions, resulting in a decrease in the

depolarizing effects of an excitatory input, thus depressing excitability. As a result, the cell is

7
inhibited, and an anticonvulsant, sedative or anxiolytic activity is achieved. In addition to

GABA-binding sites, the GABAA receptor possesses binding sites for other compounds,

including benzodiazepines and barbiturates, that can allosterically modify the chloride

channel gating of GABA (Diniz et al., 2015; Jäger and Saaby, 2011; Wasowski and Marder,

2012). Several flavonoids (e.g., apigenin, naringenin) bind to the so-called benzodiazepine

site and sensitize the receptor to GABA, increasing the GABA-induced chloride channel

opening frequency. These compounds can be effective in treating anxiety, insomnia and

epilepsy and have muscle relaxant, sedative hypnotic and cognition-impairing effects.

Flavonoids, including kaempferol, quercetin, apigenin, isoquercitrin, rutin, and naringenin,

are inhibitors of monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) and

may be useful in treating depression and Parkinson’s disease (Jäger and Saaby, 2011). The

many mechanisms of action of flavonoids indicate their potential use for the treatment of

Alzheimer’s and Parkinson’s diseases. Flavonoids have antioxidant and anti-inflammatory

properties and can modulate signalling pathways. Flavonoids interact with the extracellular

signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen

activated protein kinase (MAPK) pathways. Flavonoids disrupt amyloid β aggregation and

affect amyloid precursor protein processing through inhibition of β-secretase (BACE-1)

and/or activation of α-secretase (ADAM10). Furthermore, flavonoids act on the vascular

system, potentially leading to the enhancement of cognitive performance through increased

cerebral blood flow, which induces angiogenesis and neurogenesis in the hippocampus

(Bakhtiari et al., 2017; Kujawska and Jodynis-Liebert, 2018; Magalingam et al., 2015;

Spencer, 2009; Williams and Spencer, 2012). Moreover, the anxiolytic activity of flavonoids

has also been demonstrated, including kaempferol, quercetin and luteolin (Aguirre-Hernández

et al., 2016; Karim et al., 2018). It was confirmed that flavonoids exhibit neuroprotective

activity due to their ability to inhibit cholinesterase (Spencer, 2009). A flavanone isolated

8
from Viscum album L., 5,7-dimethoxyflavanone-4’-O-[5’’’-O-trans-cinnamoyl-β-D-

apiofuranosyl]-β-D-glucopyranoside, inhibited acetylcholinesterase by 22.3 ± 2.1 % and

butyrylcholinesterase by 46.0 ± 1.9 % (Orhan et al., 2014). Flavonoid derivatives isolated

from Viscum album L. growing on Armeniaca vulgaris Lam. (Rosaceae) (apricot), 2’-

hydroxy-4’,6’-dimethoxy-chalcone-4-O-β-D-glucopyranoside and 5,7-dimethoxy-flavanone-

4’-O-[β-D-apiofuranosyl-(1→2)]-β-D-glucopyranoside (30 mg/kg), showed antinociceptive

activity in the p-benzoquinone-induced writhing test in mice, but the activity was not as

strong as that of the standard drug ASA (100 mg/kg) (Orhan et al., 2006). The

neuropharmacological effects of phenolic acids were also studied, including ferulic, caffeic,

chlorogenic, rosmarinic, p-coumaric, sinapic, salicylic, protocatechuic, gallic, syringic and

ellagic acids. Similar to flavonoids, their activity is mediated by various mechanisms of action

and they may be used to treat depression, epilepsy, Parkinson’s disease and amnesia

(Szwajgier et al., 2017). Some sterols have also shown activity on the CNS (Chang et al.,

2013) by crossing the blood-brain barrier (Vanmierlo et al., 2015). Stigmasterol was found to

reduce amyloid β generation by decreasing β-secretase activity, reducing the expression of all

γ-secretase components, reducing the cholesterol and presenilin distributions in lipid rafts

implicated in amyloidogenic amyloid precursor protein (APP) cleavage and decreasing

BACE-1 internalization to the endosomal compartments involved in APP β-secretase

cleavage (Burg et al., 2013). Furthermore, stigmasterol can upregulate genes involved in

neurogenesis and synaptogenesis (Haque and Moon, 2018) as well as reverse ketamine-

induced behavioural changes, increase GABA, reduce glutathione levels and decrease

dopamine, malondialdehyde, TNF-α levels, it can also decrease acetylcholinesterase activity

in mice, and all these factors are involved in the pathogenesis of psychosis (Yadav et al.,

2018). A lignan, syringaresinol, was able to suppress excitatory synaptic transmission by

modulating presynaptic transmitter release and suppressing picrotoxin-induced epileptiform

9
activity in the hippocampal slices of the mouse brain (Cho et al., 2018). Furthermore,

syringaresinol (10 and 20 mg/kg) isolated from the methanolic fraction of Viscum articulatum

Burm. f., another mistletoe species, exhibited dose-dependent activity against picrotoxin- and

NMDA-induced seizures in rats and mice (Geetha et al., 2018). Additionally, terpenoids are

neuroprotective (Parmar et al., 2013). Ursolic acid was found to be effective against D-

galactose-induced neurotoxicity in mice, the mechanism of which may be connected to an

increase in the activity of antioxidant enzymes and a reduction in lipid peroxidation.

Furthermore, ursolic acid inhibited the activation of caspase-3 induced by D-galactose and

increased the level of growth-associated protein GAP43 in the brain of D-galactose-treated

mice. Behavioural tests showed that ursolic acid reversed D-galactose-induced learning and

memory impairment (Lu et al., 2007). Ursolic acid had sedative, anticonvulsant and analgesic

activity in mice, which may be connected with opioid receptors and the anti-inflammatory and

antioxidant effects of this compound (Taviano et al., 2007). Betulin was found to be effective

against bicuculline-induced seizures in connection with its binding to the GABAA-receptor

sites in the mouse brain (Muceniece et al., 2008). α-Terpineol increased the latency to

convulsions induced by pentylenetetrazole (PTZ) and decreased the incidence of hind limb

extension produced by maximal electroshock (MES) (De Sousa et al., 2007). Carvacrol and

(−)-borneol increased the latency of convulsions induced by PTZ and prevented the tonic

convulsions induced by MES in mice. It was suggested that the GABAergic neurotransmitter

system may be involved in the effects of borneol (Quintans-Júnior et al., 2010). Phytol was

active against seizures induced by pilocarpine, the effect of which was not blocked by

pretreatment with flumazenil, an antagonist of benzodiazepine receptors (Costa et al., 2012).

Behavioural tests in mice showed that a mixture of α- and β-amyrin exhibited sedative and

anxiolytic effects that may involve the action of benzodiazepine-type receptors, while the

antidepressant effect may be connected with noradrenergic mechanisms (Aragão et al., 2006).

10
We assume that mistletoe compounds do not manifest their neuropharmacological activity

alone as isolated chemicals. Mistletoe compounds act in combination with other compounds

and have synergic actions. The interactions of mistletoe-specific lectins may involve

compounds from other groups, including flavonoids, phenolic acids or terpenoids. It is

possible that compounds isolated from mistletoe are ubiquitous in other plants and that

mistletoe has unique combinations that produce CNS activity. Investigating the mechanisms

of action of mistletoe compounds on the CNS is a subject for further studies and a new field

for scientists.

3. Mistletoe in the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss

of mental, behavioural, functional, and cognitive abilities (Kumar et al., 2015; Masters et al.,

2015). AD is associated with neuronal loss connected with altered levels of brain-derived

neurotrophic factor (BDNF). BDNF is a neurotrophin that promotes neuronal survival and

neurogenesis. It was reported that a 21-day treatment with an aqueous extract of leaves of

Viscum album L. growing on an orange tree (Rutaceae: Citrus sinensis (L.) Osbeck) (100

mg/kg) may increase BDNF in mice with aluminium chloride-induced Alzheimer’s disease

with the simultaneous administration of AlCl3 (150 mg/kg). Moreover, the BDNF levels were

increased in mice treated with the same extract 10 days after administration of AlCl3.

Furthermore, histological studies of the cerebral cortex (treated with aluminium chloride and

the extract) revealed that the extract enhanced neuronal density and population size

(Ekpenyong et al., 2016). Another study showed that a 21-day treatment with an aqueous

extract of leaves of Viscum album L. growing on an orange tree (100 mg/kg) and AlCl3 (150

mg/kg) beginning 10 days after AlCl3 administration reduced aluminium chloride-induced

memory impairment and oxidative damage (Ademola et al., 2016). The accumulation of β-

amyloid and formation of an extracellular senile plaque are the major causes of Alzheimer’s

11
disease. Methanolic and ethanolic extracts of Viscum album subsp. coloratum Kom. were

examined for amyloid β- (10 µM) and hydrogen peroxide- (100 µM) induced neurotoxicity in

cultured rat cortical neurons, respectively. The methanolic extract of the plant (10, 30 and 50

µg/ml) significantly prevented amyloid β–induced apoptotic neuronal death. The ethanolic

extract (10-100 µg/ml) inhibited hydrogen peroxide–induced neuronal cell death in a dose-

dependent manner, as assayed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium

bromide (MTT) and Hoechst 33342 staining. The mechanism may be connected with an

increase in the intracellular calcium concentration, inhibition of glutamate release and

generation of reactive oxygen species (ROS) in cultured neurons (Jang et al., 2015; Lee et al.,

2007). Additionally, a 7-day treatment with a methanolic extract of Viscum album subsp.

coloratum Kom. (25 and 50 mg/kg) significantly protected against the memory impairment

induced by an intracerebroventricular injection of amyloid β (8 nmol) in mice (Jang et al.,

2015). It has been suggested that Alzheimer’s disease may be caused by a deficiency of

acetylcholine in the brain. There is a search for new acetylcholinesterase and

butyrylcholinesterase inhibitors, which may be the most useful drug candidates for the

treatment of this illness. Aqueous, methanolic and dichloromethane extracts of Viscum album

L. (200 µg/ml) collected from 12 various host trees were tested for their ability to inhibit

acetylcholinesterase and butyrylcholinesterase. All extracts exhibited a low inhibition of

cholinesterases. The highest inhibition of acetylcholinesterase was caused by an aqueous

extract of mistletoe growing on sour cherry (29.00 ±2.78 %), while a methanolic extract of

mistletoe growing on acacia was the most potent inhibitor of butyrylcholinesterase (26.30

±2.44 %). On the other hand, the same extracts were inactive in inhibiting tyrosinase

(inhibition below 7 %), which catalyses the transformation of tyrosine to dopaquinone and

may be associated with Parkinson’s disease (PD) (Orhan et al., 2014). Furthermore, 50 % and

100 % ethanolic extracts of Viscum album caused inhibition of tyrosinase below 20 % (Ju et

12
al., 2009). On the other hand, tyrosinase inhibition by hot water and ethanolic extracts of

Korean mistletoe reached 63.9 ± 0.02 % and 62.6 ± 0.01 %, respectively (Lee et al., 2013)

4. Mistletoe in the treatment of epilepsy

Epilepsy is a chronic neurological disease characterized by recurrent and unprovoked seizures

(Falco-Walter et al., 2018; Staley, 2015). An aqueous extract of leaves from Viscum album L.

growing on a citrus tree showed antiepileptic activity on mice and rats. Animals received the

extract at doses of 50 and 150 mg/kg 60 min before application of electroshock and 30 min

and 60 min before the administration of isoniazid and pentylenetetrazole (PTZ) (90 mg/kg),

respectively. Mistletoe reduced various phases of epileptic seizures induced by MES in a

dose-dependent manner in comparison with phenytoin (90 mg/kg). In an isoniazid-induced

convulsion model, the extract increased the latency to the first convulsion. Furthermore, in a

PTZ-induced convulsion model, the extract dose-dependently increased convulsion onset and

reduced seizure duration (Gupta et al., 2012). Various mistletoe extracts (100 mg/kg) were

tested against seizures induced by PTZ (80 mg/kg) in albino mice. The extracts were

administered for two days, and sodium valproate (300 mg/kg) was the standard antiepileptic

drug. Aqueous and aqueous-ethanolic extracts of Viscum album L. collected from maple and

ethanolic extract of Viscum album L. collected from willow were effective against seizures

(Tsyvunin et al., 2016).

Madeleyn, 1990 reported cases of children suffering from infantile spasms and a boy with

epilepsy who became seizure-free after treatment with Viscum album L. Furthermore, von

Schoen-Angerer et al., 2015 reported a case of a 4½-year-old girl who was suffering from

childhood absence epilepsy. Traditional treatment with antiepileptic drugs and a ketogenic

diet did not inhibit her seizures. Inhibition of her seizures was achieved after adding

complementary treatment with Viscum album L. growing on an apple tree.

13
It should be noted that antiepileptic activity has also been reported for another species of

mistletoe. A methanolic extract of South African mistletoe (Viscum capense L. f.) stems (50

and 100 mg/kg) was tested for activity against seizures induced by PTZ (95 mg/kg),

bicuculline (10 mg/kg) and N-methyl-DL-aspartic acid (NMDLA) (400 mg/kg) in albino

mice. The extract combined with the standard drugs phenobarbitone (10 and 12.5 mg/kg) and

diazepam (0.25 and 0.50 mg/kg) were administered 15 min, 10 min and 20 min before

administration of the convulsant agent. The extract at both concentrations delayed the onset of

PTZ- and bicuculline-induced seizures and reduced the number of convulsing animals. On the

other hand, the extract had moderate effect against NMDLA-induced tonic seizures

(Amabeoku et al., 1998). A methanolic extract of aerial parts of Viscum articulatum Burm. f.

was significantly active against seizures in albino rats. Rats received 100 and 200 mg/kg of

the methanolic extract for a period of seven days. Seizures were induced by MES or an

injection with PTZ (80 mg/kg) 60 min after administration of the standard drug and extract.

The methanolic extract and the standard antiepileptic drug diazepam (4 mg/kg) reduced the

duration of hind limb extension and increased the latency to convulsions (Geetha et al., 2010).

In a recent article, anticonvulsant activity was tested in two experiments. In the first

experiment, albino rats received 150 and 300 mg/kg of chloroform and methanolic extracts of

aerial parts of Viscum articulatum Burm. f. The standard drug phenobarbitone (40 mg/kg) and

extracts were administered for a period of one week, and convulsions were induced by an

injection of picrotoxin (7 mg/kg) 60 minutes after administration of the test drug. In the

second experiment, mice received dizolcipine hydrogen maleate (0.05 mg/kg) and 150 and

300 mg/kg of chloroform and methanolic extracts of the aerial parts of Viscum articulatum

Burm. f. The standard drug and extracts were administered one hour before NMDA (100

mg/kg) administration. Methanolic and chloroform extracts at both doses delayed the onset of

tonic convulsions in picrotoxin-induced seizures in rats. Only the methanolic extract

14
significantly antagonized the NMDA-induced turning behaviour in mice. Furthermore, a

significant increase in the brain GABA levels was observed in picrotoxin-induced seizures in

rats treated with the methanolic extract of Viscum articulatum Burm. f. (Geetha et al., 2018).

All of these studies suggest that the antiepileptic activity of mistletoe may involve a

GABAergic mechanism.

5. Other neurological activities of mistletoe

An aqueous extract of the leaves of Viscum album L. growing on citrus had sedative activity

in mice, reducing their locomotion. Treatment with the aqueous extract (150 mg/kg) and

diazepam (4 mg/kg) changed the locomotor activity by 71.6 ± 3.6 % and 75.4 ± 3.2 %,

respectively. Additionally, the aqueous extract at a dose of 150 mg/kg significantly increased

the onset and duration of sleep induced by pentobarbital sodium in mice (20 mg/kg), thus

confirming its sedative activity. Furthermore, the antipsychotic activity was also tested in

apomorphine-induced stereotypy and haloperidol-induced catalepsy. The aqueous extract (50

and 150 mg/kg) of Viscum album L. significantly reduced the stereotyped behaviour in rats

treated with apomorphine (1,5 mg/kg). The extract, at a dose of 150 mg/kg, potentiated the

cataleptic effect of haloperidol (1 mg/kg) in rats. Both experiments suggested that the

antipsychotic activity of the extract may be related to its anti-dopaminergic action (Gupta et

al., 2012) The neuropharmacological effects of a methanolic extract of Viscum album L. and

its ethyl acetate and 1-butanol fractions were also tested in mice. The number of entries and

time spent in open arms in the elevated plus-maze test were significantly increased after

treatment with the methanol extract (50 and 100 mg/kg) and ethyl acetate (5 and 10 mg/kg)

and 1-butanol (5 and 10 mg/kg) fractions. The effect was observed versus a control at all

doses, but a therapeutic level equivalent to the standard drug diazepam (2 mg/kg) was

achieved only at high doses. This result confirmed the anxiolytic activity of the extracts. The

antidepressant activity was measured in the despair swim test. The methanol extract (200 and

15
400 mg/kg) and its ethyl acetate fraction (25 and 50 mg/kg) reduced the duration of

immobility in mice. Only the 1-butanol fraction at a dose of 50 mg/kg had an antidepressant

effect similar to that of the standard drug imipramine (15 mg/kg). In the open field test, the

methanol extract and its fractions reduced rearing and crossings, suggesting CNS-depressant

activity. To investigate the hypnotic activity of the methanol extract (200 or 400 mg/kg) and

ethyl acetate (25 or 50 mg/kg) and 1-butanol fractions (25 or 50 mg/kg), the thiopentone

sodium induced-sleeping time assay was used. At high doses, the methanol extract and both

fractions significantly increased the duration of sleep in mice. Moreover, the methanol extract

(200 or 400 mg/kg) and ethyl acetate (25 or 50 mg/kg) and 1-butanol fractions (25 or 50

mg/kg) showed a mild antistress activity evaluated by reduction in time spent by mice in the

immobile state in the cold swim test; however, the activity was not equivalent to that of the

standard drug diazepam (1 mg/kg). To investigate the analgesic activity, the tail immersion

test was conducted by recording tail withdrawal from heat (flicking response) in mice. The

methanol extract (200 or 400 mg/kg) and ethyl acetate (25 or 50 mg/kg) and 1-butanol

fractions (25 or 50 mg/kg) showed analgesic activity compared to a control group. However,

the effect was not comparable to that of the standard drug morphine sulphate (5 mg/kg). It

was suggested that the anxiolytic and hypnotic effects of mistletoe may be due to modulation

of the GABAA receptors (Kumar et al., 2016). The p-benzoquinone-induced writhing test

showed that the ethyl acetate fraction of Viscum album L. growing on Armeniaca vulgaris

Lam. (125 and 250 mg/kg) exhibited dose-dependent antinociceptive activity in mice (Orhan

et al., 2006). Another species of mistletoe was also tested for an antinociceptive effect.

Methanolic extracts of the leaves of Viscum orientale Willd. growing on Exoecaria agallocha

L. (Euphorbiaceae) at doses of 300 and 500 mg/kg caused 65.6 % and 88.8 % writhing

inhibition, respectively, in the acetic acid-induced writhing model. This effect was similar to

the standard drug diclofenac-Na (25 mg/kg), which inhibits writhing by 75.2 %. Additionally,

16
the formalin-induced pain model showed that paw licking was inhibited by the extract at

doses of 300 and 500 mg/kg by 45.9 % and 56.4 % in the early phase and 55.7 and 72.6 % in

the late phase, respectively, while diclofenac-Na (10 mg/kg) inhibition was 60.5 % and 61.3

% in the early and late phases, respectively. It was postulated that the analgesic effect of the

extract may, in part, be related to its anti-inflammatory and neurogenic pain. Furthermore, the

extract exhibited CNS-depressing activity as measured by the open field test and hole cross

test in mice. At doses of 300 and 500 mg/kg, the extract reduced spontaneous motor activities

(Khatun et al., 2016).

6. Conclusion

Numerous historical references describe the use of mistletoe in the treatment of CNS

disorders. In recent years, studies confirming these activities have begun to appear. In vitro

and in vivo (studies in mice and rats) suggest that mistletoe is a promising herbal preparation

with antiepileptic, antipsychotic, sedative and antinociceptive activities. Additionally,

mistletoe might be able to be used as a complementary treatment in Alzheimer’s disease. To

date, the compounds responsible for these activities have not been identified due to the large

variability of the chemical composition of mistletoe preparations, which depends on the host

plant species, parts of the plant, time of harvest and methods of extraction. A therapeutic

effect may result from synergistic interactions of various secondary metabolites rather than an

individual compound. We assume that these interactions may involve mistletoe-specific

lectins and compounds from other well-known groups, such as flavonoids, phenolic acids or

terpenoids. It is possible that the compounds isolated from mistletoe and ubiquitous in other

plants create unique combinations in mistletoe, thus producing CNS activity. Studies of the

neuropharmacological activity of mistletoe represent a new field for scientists. More

advanced chemical research is needed to determine exact chemical composition of various

mistletoe extracts. It is necessary to perform fractionation and isolation of mistletoe

17
compounds to study their biological activity towards CNS receptors. Research to determine

the mechanism of their action and their mutual interactions must be conducted, not only in in

vitro studies but especially in in vivo studies. Once the pharmacological activity of mistletoe

compounds is studied, methods of standardization of the extracts should be developed, not

only for different species of mistletoe but also mistletoe extracts from different host trees.

Standardized extracts could be used in clinical trials to determine concentrations and

therapeutic doses of active ingredients. Such standards would also allow us to study

pharmacokinetics, metabolic mechanisms, adverse side effects and interactions with other

drugs. This knowledge will enable the safe use of mistletoe as a complementary treatment in

various neurological disorders. We hope researchers have been encouraged to study the

neuropharmacological activity of mistletoe and that we have proven that folk medicine has

much to offer to modern science in terms of valuable sources of new, effective and safe drugs.

Conflict of interest

The authors declare no financial or commercial conflict of interest.

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List of tables:

Table 1 Chemical composition of Viscum L. species

References
Group Compounds Viscum species
Misteltoe-specificcompounds

album L., coloratum (Lyu et al.,

(Kom.) Nakai 2000;
Ochocka
and
Piotrowski,
Lectins MLI, MLII, MLII, cbML1, cbML2, cbML3
2002;
Stoeva et
al., 2001;
Urech et al.,
2006)
(Hussain et
al., 2013;
Ochocka
and
Piotrowski,
2002; Orrù
Viscotoxins A1, A2, A3, B, B2, 1-PS, U-PS, C1 album L. et al., 1997;
Romagnoli
et al., 2003;
Schaller et
al., 1998;
Urech et al.,
2006)
Other well-known compounds
Flavonoids Rhamnetin, rhamnazin, 3-O-methylquercetin, album L. (Pietrzak et

35
 taxifolin al., 2017)
Rhamnetin-3-O-rhamnoside, quercetin-3-O-β-D- coloratum (Kom.) (Song et al.,
glucopyranoside-(1→6)-α-L-arabinoside, Nakai 2016)
apigenin-6,8-di-C-glucoside
Rhamnazin-3,4'-di-O-glucoside coloratum (Kom.) (Fukunaga
Nakai et al., 1989)
(2R)-5,7-dimethoxyflavanone-4'-Ο-glucoside, album L. (Fukunaga
(2S)-3',5,7-trimethoxyflavanone-4'-Ο-glucoside, et al., 1987)
2'-hydroxy-3,4',6'-trimethoxychalcone-4-Ο-
glucoside,
2'-hydroxy-4',6'-dimethoxychalcone-4-Ο-
glucoside, 2'-hydroxy-4',6'-dimethoxychalcone-4-
Ο-[apiosyl (1→2)] glucoside
Rhamnazin-3-O-β-D-glucoside, homoeriodictyol- coloratum (Kom.) Zhao et al.,
7-O-β-D-apiose (1→5)-β-D-apiose (1→2)-β-D- Nakai 2011)
glycoside, pachypodol, 5,7,4'-trihydroxy-3,3'-
dimethoxyflavone
Rhamnazin-3-O-β-D-glucoside, coloratum (Kom.) (Long et al.,
rhamnazin-3-O-β-D-(6''-β-hydroxy-β- Nakai 2017)
methyglutaryl)-β-D-glucoside-4'-O-β-D-glucoside
Isorhamnetin album L., coloratum (Lee et al.,
(Kom.) Nakai 2013;
Pietrzak et
al., 2017)
Rhamnazin-3-O-β-D-apiosyl-(1→2)-β-D-[6''-(3- coloratum (Kom.) (Li et al.,
hydroxy-3-methylglutaric methyl ester)]- Nakai 2012)
glucoside,
rhamnazin-3-O-β-D-apiosyl-(1→2)-β-D-[6''-(3-
hydroxy-3-methylglutarate)]-glucoside,
quercetin-3-O-β-D-glucoside
Rhamnazin-4'-O-β-[apiosyl (1→2)]glucoside, alni-formosanae (Chou et al.,
(2S)-5-hydroxy-7,3'-dimethoxyflavanone-4'-O-β- Hayata 1999)
[apiosyl (1→2)]glucoside
Rhamnazin-3-O-β-D-(6''-β-hydroxy-β- coloratum (Kom.) (Long et al.,
methyglutaryl)-glucoside, Nakai 2017; Zhao
5-hydroxy-3,7,3'-trimethoxyflavone-4'-O-β-D- et al., 2011)
glucoside
Kaempherol album L. (Pietrzak et
al., 2017;
Vicas et al.,
2011)
Rhamnocitrin 3-O-apiosyl(1→5)apiosyl(1→2)- angulatum B.Heyne ex (Lin et al.,
[α-L-rhamnopyranosyl(1→6)]-β-D- DC. 2002)
glucopyranoside,
pinocembrin 7-O-apiosyl(1→5)apiosyl(1→2)-β-
D-glucopyranoside
isorhamnetin-3-O-β-D-glucoside coloratum (Kom.) (Li et al.,
Nakai 2012; Zhao
et al., 2011)
Quercetin album L., coloratum (Khatun et
(Kom.) Nakai, al., 2016;
ovalifolium DC. Kumar et

36
 al., 2016;
Lee et al.,
2013; Lu et
al., 2013;
Pietrzak et
al., 2017;
Vicas et al.,
2011)
7,3',4'-Trimethylquercetin coloratum (Kom.) (Chen et al.,
Nakai 2009)
Guercetin-3-O-α-L-rhamnoside, 3',4'-O- album L. (Li et al.,
dimethyltaxifolin, 3,5,7,4'-tetrahydroxy-3'- 2011)
methoxyflavanone
3,7,3'-tri-O-methylquercetin-4'-O-β-D- album L. (Nhiem et
apiofuranosyl-(1→2)-O-β-D- glucopyranoside, al., 2013)
7,3'-di-O-methylquercetin-4'-O-β-D-
glucopyranosyl-3-O-[6'''-(3-hydroxy-3-
methylglutaroyl)]-α-D-glucopyranoside, 7,3'-di-
O-methylquercetin-4'-O-β-D-glucopyranosyl-3-
O-[(6'''''→5'''')-O-1'''''-(sinap-4-yl)-β-D-
glucopyranosyl-6'''-(3-hydroxy-3-
methylglutaroyl)]-α-D-glucopyranoside, (2S)-
homoeriodictyol-7-O –[apiofuranosyl-
(1→2)]glucopyranoside, (2S)-5-hydroxy-7,3'-
dimethoxyflavanone-4'-O-β-D-apiofuranosyl-
(1→5)-O-β-D-apiofuranosyl-(1→2)-O-β-D-
glucopyranoside, (2S)-5-hydroxy-7,3'-
dimethoxyflavanone-4'-O-β-[apiofuranosyl
(1→2)]-glucopyranoside
Hyperoside album L., coloratum (Long et al.,
(Kom.) Nakai 2017;
Trifunschi
et al., 2017)
Isoquercitrin album L. (Trifunschi
et al., 2017)
Homoeriodictyol album L.,angulatum (Leu et al.,
B.Heyne ex DC., 2006; Li et
articulatum Burm. al., 2015,
f..,coloratum (Kom.) 2012, 2011;
Nakai Lin et al.,
2002; Long
et al., 2017;
Zhao et al.,
2011)
Homoeriodictyol-7-O-[apiosyl(1→2)]glucoside coloratum (Kom.) (Fukunaga
Nakai et al., 1989;
Leu et al.,
2006)
Homoeriodictyol-7-O-β-D-apiosyl-(1→2)-β-D- coloratum (Kom.) (Li et al.,
glucoside Nakai 2012; Zhao
et al., 2011)
Homoeriodictyol-7-O-β -D-apiose-(1→2)-β-D- coloratum (Kom.) (Long et al.,

37
 glucoside Nakai 2017; Ma et
al., 2015;
Zhao et al.,
2011)
Homoeriodictyol-7-O-β-D-glucopyranoside-4'-O- articulatum Burm. f.. (Li et al.,
β-D-(5'''-cinnamoyl)apiofuranoside, 2008)
homoeriodictyol-7-O-β-D-glucopyranoside-4'-O-
β-D-apiofuranoside, pinocembrin-7-O-β-D-
apiofuranosyl(1→2)-β-D-glucopyranoside,
pinocembrin-7-O-β-D-apiofuranosyl-(1→5)-β-D-
apiofuranosyl-(1→2)-β-D-glucopyranoside,
pinocembrin-7-O-cinnamoyl (1→5)-β-D-
apiofuranosyl (1→2)]-β-D-glucopyranoside,
5,3',4'-trihydroxyflavanone-7-O-β-D-
glucopyranoside, 4'-hydroxy-7,3'-
dimethoxyflavan-5-O-β-D-glucopyranoside
Pinocembrin-7-O-β-D-glucopyranoside articulatum Burm. f.. (Kuo et al.,
2010; Li et
al., 2008)
Homoeriodictyol-7-O-β-D-glucopyranoside articulatum Burm. f.., (Kuo et al.,
2010; Li et
al., 2011,
2008)
Homoeriodictyol-7-O-β-D-glucoside articulatum Burm. f.., (Li et al.,
coloratum (Kom.) 2015, 2012;
Nakai Long et al.,
2017; Ma et
al., 2015;
Zhao et al.,
2011)
(2S)-homoeriodictyol-7-O-glucoside, (2S)- coloratum (Kom.) (Leu et al.,
naringenin-7-O-glucoside, (2S)-pinocembrin-7-O- Nakai 2006)
glucoside, (2S)-pinocembrin-7-O-[apiosyl(1→2)]-
glucoside, (2S)-pinocembrin-7-O-
[cinnamoyl(1→5)-apiosyl(1→2)]glucoside, (2S)-
pinocembrin, (2S)-5,3',4'-trihydroxyflavanone-7-
O-glucoside, (2S)-5,7,3',4'-tetrahydroxyflavanone,
(2S)-7,4'-dihydroxy-5,3'-dimethoxyflavanone
Homoeriodictyol-7-O-β-D-apiosyl-(1→5)-β-D- coloratum (Kom.) (Li et al.,
apiosyl-(1→2)-β-D-glucoside Nakai 2012; Ma et
al., 2015)
(2S)-homoeriodictyol-7-O-β-D-apiofuranosyl- album L. (Thu et al.,
(1→2)-O-β-D-glucopyranoside, (2S)-5-hydroxy- 2016)
7,3'-dimethoxyflavanone-4'-O-β-D-apiofuranosyl-
(1→2)-O-β-D-glucopyranoside
Homoeriodictyol-7-O-β-apiosyl-(1→2)-O-β- coloratum (Kom.) (Park et al.,
glucoside, Nakai 2017)
homoeriodictyol-7-O-β-apiosyl-(1→5)-O-β-
apiosyl-(1→2)-O-β-glucoside
Viscumneoside V album L.,angulatum (Lin et al.,
B.Heyne ex DC. 2002;
Nhiem et

38
 al., 2013)
Naringenin album L., angulatum (Leu et al.,
B.Heyne ex DC., 2006; Li et
articulatum Burm. al., 2015,
f..,coloratum (Kom.) 2011; Lin et
Nakai al., 2002;
Pietrzak et
al., 2017)
Naringenin-7-O-β-D-glucopyranoside, articulatum Burm. f.. (Kuo et al.,
eriodictyol-7-O-β-D-glucopyranoside, visartiside 2010)
A, visartiside B, visartiside C
Naringenin-7-O-β-D-glucoside, pinocembrin-7- articulatum Burm. f.. (Li et al.,
O-β-D-glucoside, eriodictyol-7-O-β-D-glucoside, 2015)
2R/2S-viscarticulide A, 2R/2S-viscarticulide B,
2R/2S-viscarticulide C
Eriodictyol album L., articulatum (Li et al.,
Burm. f.., coloratum 2015, 2011;
(Kom.) Nakai, Long et al.,
liquidambaricola 2017;
Hayata Pietrzak et
al., 2017;
Yang et al.,
2005)
Apigenin album L. (Kumar et
al., 2016;
Pietrzak et
al., 2017)
Flavoyadorinin-B coloratum (Kom.) (Fukunaga
Nakai et al., 1989;
Long et al.,
2017)
homo-flavoyadorinin-B album L.,coloratum (Fukunaga
(Kom.) Nakai et al., 1989;
Nhiem et
al., 2013;
Thu et al.,
2016)
Luteolin album L., coloratum (Lee et al.,
(Kom.) Nakai 2013;
Pietrzak et
al., 2017;
Trifunschi
et al., 2017)
Rutin album L., ovalifolium (Lu et al.,
DC. 2013;
Trifunschi
et al., 2017;
Tsyvunin et
al., 2016)
5,4'-dihydroxyflavanone-7-O-β-D- album L., articulatum (Li et al.,
glucopyranoside Burm. f.. 2011, 2008)
5,7-dimethoxy-4'-hydroxy flavanone, 4',5- album L. (Choudhary

39
 dimethoxy-7-hydroxy flavanone, 4'-O-[β-D- et al., 2010)
apiosyl(1→2)]-β-D-glucosyl]-5-hydroxyl-7-O-
sinapylflavanone
5,7-dimethoxy-4'-O-β-D- album L. (Choudhary
glucopyranosideflavanone et al., 2010;
Orhan et al.,
2006, 2002)
5,7-dimethoxy-flavanone-4'-O-[β-D- album L. (Deliorman
apiofuranosyl(1→2)]-β-D-glucopyranoside et al., 2000;
Orhan et al.,
2006, 2002)
5,7-dimethoxy-flavanone-4'-O-[2''-O-(5'''-O-trans album L. (Orhan et
-cinnamoyl)-β-D-apiofuranosyl]-β-D- al., 2006,
glucopyranoside, 2'-hydroxy-4',6'- 2002)
dimethoxychalcone-4-O-β-D-glucopyranoside, 2'-
hydroxy-4',6'-dimethoxychalcone- 4-O-[2''-O-
(5'''-O-trans -cinnamoyl)-β-D-apiofuranosyl]-β-D-
glucopyranoside
5,7-dimethoxyflavanone-4'-O-[5'''-O-trans- album L. (Orhan et
cinnamoyl-β-D-apiofuranosyl]-β-D- al., 2014)
glucopyranoside
Sakuranetin album L. (Melo et al.,
2018;
Pietrzak et
al., 2017)
Isosakuranetin album L. (Melo et al.,
2018)
Chrysin coloratum (Kom.) (Long et al.,
Nakai,liquidambaricol 2017; Yang
a Hayata et al., 2005)
3'-Methoxyapiin album L. (Nhiem et
al., 2013;
Thu et al.,
2016)
Phenolic acids Gentisic acid, isochlorogenic acid, chlorogenic album L., coloratum (Amer et al.,
acid, neochlorogenic acid, coumaric acid, p- (Kom.) Nakai, 2013;
coumaric acid, m-coumaric acid, trans-m- liquidambaricola Khatun et
coumaric acid, o-coumaric acid, sinapic acid, Hayata al., 2016;
trans-cinnamic acid, cinnamic acid, gallic acid, Lee et al.,
digallic acid, p-hydroxybenzoic acid, 2013; Leu et
protocatechuic acid, caffeic acid, syringic acid, al., 2006;
isoferulic acid, ferulic acid, rosmarinic acid, Long et al.,
veratric acid, vanillic acid, salicylic acid, ellagic 2017;
acid Łuczkiewic
z et al.,
2001; Melo
et al., 2018;
Pietrzak et
al., 2017;
Trifunschi
et al., 2017;
Tsyvunin et

40
 al., 2016;
Vicas et al.,
2011; Yang
et al., 2005)
Sterols β-Sitosterol, γ-sitosterol album L., coloratum (Leu et al.,
(Kom.) Nakai, 2006; Long
ovalifolium DC. et al., 2017;
Lu et al.,
2013;
Urechet al.,
2005; Vlad
et al., 2016)
β-Sitosteryl-3-β-D-glucoside, stigmasteryl-3-β-D- coloratum (Kom.) (Leu et al.,
glucoside Nakai 2006)
Stigmasterol album L., coloratum (Leu et al.,
(Kom.) Nakai 2006; Urech
et al., 2005;
Vlad et al.,
2016)
Campesterol album L. (Vlad et al.,
2016)
Phytosterol, phytosterol-β-D-glucoside album L. (Fukunaga
et al., 1987)
Daucosterol album L. (Li et al.,
2011)
Lignans Alangilignoside C, (7R,8S,8'S)-4,9,4'-trihydroxy- album L. (Melo et al.,
3,5,3',5'-tetramethoxy-7,9'-epoxylignan 9-O-β-D- 2018;
glucopyranoside (ligalbumoside A) , Nhiem et
(7S,8S,7'S,8'R)-4,9,4’-trihydroxy-3,5,3',5',7'- al., 2012)
pentamethoxy-7,9'-epoxylignan 9-O-β-D-
glucopyranoside (ligalbumoside B),
(7R,8R,7'S,8'S)-4,9,4'-trihydroxy-3,5,3',5',7'-
pentamethoxy-7,9'-epoxylignan 9-O-β-D-
glucopyranoside (ligalbumoside C),
(7S,8R,7'S,8'R)-4,9,4'-trihydroxy-3,5,3',5',7'-
pentamethoxy-7,9'-epoxylignan 9-O-β-D-
glucopyranoside (ligalbumoside D),
(7R,8S,7'R,8'S)-4,9,4',7'-tetrahydroxy-3,5,3',5'-
tetramethoxy-7,9'-epoxylignan 9-O-β-D-
glucopyranoside(ligalbumoside E)
Syringaresinol album L., coloratum (Chen et al.,
(Kom.) Nakai 2009;
Geetha et
al., 2018; Li
et al., 2011;
Long et al.,
2017)
(+)-Syringaresinal-4'-O-β-D-glucopyranoside, album L. (Li et al.,
curuilignan D 2011)

(+)-Pinoresinol album L., coloratum (Chen et al.,

(Kom.) Nakai 2009; Li et

41
 al., 2011;
Nhiem et
al., 2013)
(-)-Lyoniresinol 3α-O-β-D-glucopyranoside, (+)- album L. (Nhiem et
lyoniresinol 3α-O-β-D-glucopyranoside, al., 2013)
Terpenoids album L., angulatum (Delebinski
B.Heyne ex DC., et al., 2015;
articulatum Burm. f.., Fukunaga et
coloratum (Kom.) al., 1987;
Nakai, ovalifolium DC. Jadhav et
al., 2010;
Jadhav et
al., 2010;
Kim et al.,
2015; Ko et
al., 2016;
Leu et al.,
2006; Li et
Betulinic acid
al., 2011;
Lu et al.,
2013;
Nhiem et
al., 2013;
Urech et al.,
2005; Vicas
et al., 2011;
Wójciak-
Kosior et
al., 2016;
Yang et al.,
2009)
coloratum (Kom.) (Chen et al.,
3-epi-Betulinic acid Nakai 2009; Yang
et al., 2009)
album L., angulatum (Delebinski
B.Heyne ex DC., et al., 2015;
articulatum Burm. f.., Fukunaga et
coloratum (Kom.) al., 1987;
Nakai, Jadhav et
liquidambaricola al., 2010;
Hayata, ovalifolium Jadhav et
DC. al., 2010;
Oleanolic acid Kim et al.,
2015; Ko et
al., 2016;
Leu et al.,
2006; Li et
al., 2011;
Long et al.,
2017; Lu et
al., 2013;
Nhiem et

42
 al., 2013;
Song et al.,
2016;
Urechet al.,
2005;
Wójciak-
Kosior et
al., 2016;
Yang et al.,
2009, 2005)
coloratum (Kom.) (Jung et al.,
epi-Oleanolic acid
Nakai 2004)
album L., coloratum (Ko et al.,
(Kom.) Nakai 2016; Li et
Betulin al., 2011;
Vlad et al.,
2016)
album L. (Tsyvunin
et al., 2016;
Ursolic acid
Urech. et
al., 2005)
album L., ovalifolium (Lu et al.,
DC. 2013;
Urech, et
β-Amyrin
al., 2005;
Vlad et al.,
2016)
album L., coloratum (Fukunaga
(Kom.) Nakai et al., 1987;
Leu et al.,
2006;
β-Amyrin acetate Nhiem et
al., 2013;
Urech et al.,
2005; Yang
et al., 2009)
album L., coloratum (Leu et al.,
(Kom.) Nakai, 2006; Li et
ovalifolium DC. al., 2011;
Lu et al.,
Lupeol
2013; Urech
et al., 2005;
Vlad et al.,
2016)
album L., ovalifolium (Lu et al.,
DC. 2013; Urech
Lupeol acetate et al., 2005;
Vlad et al.,
2016)
album L. (Vlad et al.,
Lupenyl acetate
2016)
(3β)-Olean-12-ene-3,23-diol coloratum (Kom.) (Yang et al.,

43
 Nakai 2009)
album L., coloratum (Nhiem et
(Kom.) Nakai al., 2013;
Erythrodiol
Yang et al.,
2009)
coloratum (Kom.) (Chen et al.,
Nakai 2009; Long
Betulonic acid et al., 2017;
Yang et al.,
2009)
α-Terpineol, carvone, trans-verbenol, cis- album L. (Kürkçüoǧl
verbenol, linalool, carvacrol, trans-carveol, u et al.,
borneol, 14-hydroxy-β-caryophyllene, geraniol, 2002)
thymol, widdrol, verbenone, camphor, trans-β-
bergamotene
(-)-Loliolide, vomifoliol, trans-α-bergamotene album L. (Ćebović et
al., 2008)
Phytol,trans-phytol album L., ovalifolium (Chen et al.,
DC. 2013;
Nhiem et
al., 2013)
Loliolide coloratum (Kom.) (Chen et al.,
Nakai 2009)
Diarylheptanoid (3S,5R)-3-hydroxy-5-methoxy-1,7-bis(4- album L. (Nhiem et
s hydroxyphenyl)-6E-heptene, (3S,5S)-3-hydroxy- al., 2013)
5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene,
(3S)-3-hydroxy-1,7-bis(4-hydroxyphenyl)-6E-
hepten-5-one
1,7-di-(p-hydroxyphenyl)-5-hydroxyl-cis-2,3- coloratum (Kom.) (Yao et al.,
epoxy-1-one Nakai 2007)
1,7-di-(3',4'-dihydroxyphenyl)-4-hepten-3-one cruciatum Sieber ex (Martín-
Boiss. Cordero et
al., 2001)
Centrolobol, acerogenin G album L. (Li et al.,
2011)
Phenylpropanoi Coniferin album L. (Deliorman
d glycosides et al., 2000,
1999; Orhan
et al., 2002;
Panossian et
al., 1998)
Coniferylalcohol-4-O-β-D-apiofuranosyl (1→2)- album L. (Panossian
β-D-glucopyranoside, et al., 1998)
syringenin 4-O-β-D-apiofuranosyl (1→2)-β-D-
glucopyranoside
Kalopanaxin D album L. (Deliorman
et al., 2000,
1999; Orhan
et al., 2002)
Syringin album L., coloratum (Deliorman
(Kom.) Nakai et al., 2000,
1999;

44
 Fukunaga et
al., 1987;
Long et al.,
2017; Ma et
al., 2015;
Nhiem et
al., 2013;
Orhan et al.,
2014, 2002;
Panossian et
al., 1998)
Syringenin 4-O-glucoside, syringenin 4-O- album L. (Melo et al.,
apiosyl-glucoside 2018)
Syringenin 4'-O-β-D-apiofuranosyl-(1→2)-β-O- album L. (Nhiem et
D-glucopyranoside al., 2013)
Alkaloids Retamine, lupanine, 5,6-dehydrolupanine, cruciatum Sieber ex (Martín-
cytosine, N-methylcytisine, ammodendrine Boiss. Cordero et
al., 1997;
Martin
Cordero et
al., 1993)
4,5,4'-trihydroxy-3,3'-iminodibenzoic acid, album L. (Amer et al.,
4,5,4',5'-tetrahydroxy-3,3'-iminodibenzoic acid 2012)
Carboxylic and p-Hydroxyphenylacetic acid articulatum Burm. f.. (Li et al.,
fatty acids 2015)
Hexanoic acid, heptanoic acid, octanoic acid, album L. (Kürkçüoǧl
nonanoic acid, decanoic acid u et al.,
2002)
Undecanoic acid, Z-7-hexadecenoic acid, cis-10- album L. (Vlad et al.,
nonadecenoic acid, cis-11-eicosenoic acid 2016)
Oleic acid, linoleic acid, palmitic acid, stearic album L. (Ćebović et
acid al., 2008;
Orhan and
Orhan,
2006; Urech
et al., 2005;
Vlad et al.,
2016)
Cerotic acid, lignoseric acid, behenic acid, album L. (Orhan and
arachidic acid, montanic acid Orhan,
2006)
Monosaccharide Arabinose, xylose, glucose, galactose, mannose album L. (Arda et al.,
2003)
Polysaccharides VCP1, VCP2, VCP3 coloratum (Kom.) (Chai and
Nakai Zhao, 2016)
Polyols Xylitol, inositol album L. (Arda et al.,
2003)
Other 1-O-benzyl-[5-O-benzoyl-β-D- articulatum Burm. f.. (Li et al.,
apiofuranosyl(1→2)]-β-D-glucopyranoside 2008)
3-(4-acetoxy-3,5-dimethoxy)-phenyl-2E- album L. (Choudhary
propenyl-β-D-glucopyranoside, et al., 2010)
3-(4-hydroxy-3,5-dimethoxy)-phenyl-2E-

45
 propenyl-β-D-glucopyranoside
2',3',4',3''-tetramethoxy-1,3-diphenylpropane angulatum B.Heyne ex (Lin et al.,
5',4''-di-O-β-D-glucopyranoside DC. 2002)
2,6-dimethylocta-2,7-diene-1,6-diol 6-O-[6’-O-β- album L. (Deliorman
D-apiofuranosyl]-β-D-glucopyranoside et al., 2001)
5,7-dihydroxychromone album L., coloratum (Leu et al.,
(Kom.) Nakai 2006; Li et
al., 2011)
5-hydroxychromone-7-O-glucoside, 4- coloratum (Kom.) (Leu et al.,
hydroxybenzaldehyde, syringaldehyde, methyl-3- Nakai 2006)
O-feruloylquinate, 4-O-cinnamoylquinic acid,
vanillin, β-sitostenone, acetovanillone, 2,6-
dimethoxy-p-benzoquinone, 2-deoxy-epi-inositol,
thymine, uracil
3-(3'-carbomethoxypropyl) gallic acid, 3-(3'- album L. (Amer et al.,
carbomethoxypropyl)-7→3''- 2013)
protocatechoylgalloate
Benzaldehyde, 3-methyl-1-butanal album L. (Kürkçüoǧl
(isovaleraldehyde), phenylacetaldehyde, hexenal, u et al.,
heptanal, octanal, nonanal, (E)-2-decenal, (E)-2- 2002)
nonenal, (E)-2-octenal, (E)-2-undecanal,
undecanal, dodecanal, 2-decanone, 2-undecanone,
pentanol, hexanol, 2-ethyl-hexanol, octanol,
(E,Z)-2,4-decadienal, (E,E)-2,4-decadienal, (E,Z)-
2,4-heptadienal, (E,E)-2,4-heptadienal, (E,E)-2,4-
nonadienal, (Z)-trans-α-bergamotol, 2-pentyl
furan, 3,4-dimethyl-5-pentylidene-2(5H)-
furanone, methyl hexadecanoate, cedrol, santane,
α-pinene, β-pinene, camphene, 2-nonanone, butyl
benzene, m-xylene, 2-heptanone, 2-octanone,
limonene, 6-methyl-5-hepten-2-one, 3-octen-2-
one, 3-nonen-2-one, trans-linalool-oxide
(furanoid), 1-octen-3-ol, (E,E)-3,5-octadien-2-
one, tetramethylpyrazine, 3,5-octadien-2-one, 6-
methyl-3,5-heptadien-2-one, pinocarvone,
nopinone, terpinen-4-ol, neoisomenthol, widdrene
(thujopsene), myrtenal, pulegone, trans-
pinocarveol, p-mentha-1,5-dien-8-ol, naphtalene,
(E)-anethol, p-cymen-8-ol, benzylacetone, 1-
methyl naphthalene, methyl eugenol, trans-β-
ionone-5,6-epoxide, (E)-geranyl acetone, γ-
octalactone, γ-nonalactone
5,7,8-trimethyl-2-chromanone, 4,4,5,8- album L. (Vlad et al.,
tetramethylchroman-2-ol, α-tocopherol, 2016)
pentadecanal, 3-isopropenyl-2-
methylcyclohexanol, 1-heptatriacotanol, behenic
alcohol, 2-cis-9-octadecenyloxyethanol, 2,4-
decadienal, 4-[2,6,6-trimethyl-5-cyclohexen-1-
yl)-2-butanone, 4-(2,3,6-trimethylphenyl)2-
butanone, 4-(2,4,4-trimethyl-cyclohexa-1,5-
dienyl) but-3-en-2-one, 2-methyl-4-(2,6,6-
trimethylcyclohex-1-enyl) but-2-en-1-ol, 1-(2,6,6-

46
 trimethyl-cyclohex-1-enyl_-butane-1,3-dione,
4,4,5,6,8-pentamethyl-3,4-2H-coumarin, 1,1,4a-
trimethyl-3,4,4a,5,6,7-hexahydro-2(1H)-
naphthalenone, 1,1,6-trimethyl-1,2-
dihydronaphthalene, 3,3-dimethyl-1,2,3,4-
tetrahydro-1,2-naphthalenediol, 2,5,8-trimethyl-
1,2-dihydronaphthalene, 1,2-naphthalene diol, 3',
8, 8'-trimethoxy-3-piperidin-1-yl-2,2'-binaphthyl-
1,1,4,4’-tetrone, syringol, cendran-8,13-diol,
1,2,4-cyclopentanetrione, (-)-calamenene, 4,47a-
trimethyl-5,6,7,7a-tetrahydro-1-benzofuran-
2(4H)-one, 16-heptadecen-2,5,8-trione, 3,3,5,6-
tetramethyl-1-indanone, 3-oxo-7,8-dihydro-α-
ionol, 8,9-dehydro-neoisolongifolene, Z-9-
pentadecenol, pentadecanoic acid, 14-methyl,
methyl ester, pentadecanoic acid 13-methyl
methyl ester, (2E)-3,7,11,15-tetramethyl-2-
hexadecen-1-ol, i-propyl-9-hexadecenoate, 9-
tetradecenoic acid trimethylsilyl ester, palmitic
anhydride, 3-deoxyestradiol, α-glycerol
linolenate, methyl 5,11,14-eicostrienoate,
6,9,12,15-docosatetraenoic acid methyl ester, 17-
pentatriacontene, 4,4,6a,6b,8a,11,14b-octamethyl-
1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b
-
octadecahydro-2H-picen-3-one, (3E,5E)-7-
isopropyl-8-methyl-3,5,7-nonatrien-2-one, cedr-8-
en-13-ol, L-celemene, 2,2,3,3-tetramethyl-1-
indanone, methyl-4-(3-hydroxy-3-methyl-1-
butynyl) benzoate, azulol, 1,3-
dimethylpyrido[3,2-d]pyrimidine-2,4-(1H,3H)-
dione, 7,8-dehydro-8a-hydroxy isolongifolene,
myristic acid anhydride, E-2-methyl-3-tetradecen-
1-ol acetate, cis-10-heptadecenoic acid methyl
ester, 2,3-dihydroxypropyl elaidate, 2-tert-butyl-
6-[(3-tert-butyl-2-hydroxy-5-
methylphenyl)methyl]-4-methyl-phenol, 17-
pentatriacontene, 5-(7a-isopropenyl-4,5-dimethyl-
octahydroinden-4-yl)-3-methyl-pent-2-enal,
lanosterol, δ7-chondrillastenol
Benzeneacetaldehyde, hexacosane, undecane, (E)- ovalifolium DC. (Chen et al.,
2-hexenal, 1-octanol, chlorobenzene, 1,3- 2013)
dichloro-benzene, dihydroedulan II (cis), 6,8-
nonadien-2-one, 6-methyl-5-(1-
methylethylidene)-, trans-β-damascenone, 2-
(acetylmethyl)-(+)-3-carene, trans-
geranylacetone, 3,5-di-tert-butylphenol, 9-
octadecyne, phytone, phthalic acid, isobutyl
isoporpyl ester, dibutyl phthalate, furfurol
n-Tricosane, n-tetracosane, n-pentacosane, n- album L. (Ćebović et
hexacosane, n-heptacosane, n-octacosane, n- al., 2008)
nonacosane (celidoniol), n-triacontane, γ-

47
 tocopherol (vitamin E), 1H-2-benzopyrane-1-
on,3,4-dihydro-8-hydroxy-3-methyl-(CAS)
isocoumarine, 2(4H)-benzofuranone-5,6,7,7a-
tetrahydro-4,4,7a-trimethyl-(R) aktinidiolid,
2-pentadecanone-6,10,14-trimethyl-(CAS)
hexahydrofarnesyl acetone, trans-β-farnesene,
fytol, 9-tricosene,(Z)-(CAS), muscalure, 4,8,12-
trimethyltridecane-4-olid, ergosta-5,7,22-trien-3-
ol
Liquidamboside coloratum (Kom.) (Long et al.,
Nakai, 2017; Yang
liquidambaricola et al., 2005)
Hayata
Phenylalanine, astragaloside IV, isornetin-3-O-D- coloratum (Kom.) (Long et al.,
glucoside, coumarin Nakai 2017)
(+)-Medioresinol, nerolidol album L. (Nhiem et
al., 2013)
Viscolin coloratum (Kom.) (Leu et al.,
Nakai 2006; Liang
et al., 2011)
Hentriacontanol articulatum Burm. f.. (Geetha et
al., 2018)
Hexahydrofarnesyl acetone album L. (Kürkçüoǧl
u et al.,
2002; Vlad
et al., 2016)
β-Ionone album L., ovalifolium (Chen et al.,
DC. 2013;
Kürkçüoǧlu
et al., 2002)
1-Octadecene, ethyl palmitate, 28-hydrxy- ovalifolium DC. (Lu et al.,
amyrone, β-amyrinpalmitate 2013)
Adenosine, thymidine, syringing, 1,5-dimethyl- coloratum (Kom.) (Park et al.,
6,8-dioxatricyclo[4.2.1.03,9]nonane-3-methyl-2,4- Nakai 2017)
pentadienoic acid
Visartiside D, visartiside E, visartiside F, (4'- articulatum Burm. f.. (Kuo et al.,
hydroxy-2',3',6',3''-tetramethoxy-1,3- 2010)
diphenylpropane)-4''-O-β-D-glucopyranoside

48