Therapeutic potential of mistletoe in CNS-related neurological disorders and the chemical composition of Viscum species

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: DOI: Reference:

S0378-8741(18)32801-0 https://doi.org/10.1016/j.jep.2018.11.025 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 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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: [email protected] e-mail: [email protected] e-mail: [email protected] *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:

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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

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

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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

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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 peroxideinduces 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

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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).

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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 galactosespecific 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 acetylgalactosaminespecific 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 (ML1) 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 GABAgated 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

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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-flavanone4’-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 ketamineinduced 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

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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 Dgalactose-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).

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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 βamyloid 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 dosedependent 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.

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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

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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

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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,

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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

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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. References Ademola, O., Edem, E., Olufunke, D., Oladunni, K., 2016. Cognitive-enhancing and neurotherapeutic prospects of Viscum album in experimental model of Alzheimer’s disease. African J. Cell. Pathol. 7, 11–16. Aguirre-Hernández, E., González-Trujano, M.E., Terrazas, T., Santoyo, J.H., Guevara-Fefer, P., 2016. Anxiolytic and sedative-like effects of flavonoids from Tilia americana var. mexicana: GABAergic and serotonergic participation. Salud Ment. 39, 37–46. https://doi.org/10.17711/SM.0185-3325.2015.066 Amabeoku, G.J., Leng, M.J., Syce, J.A., 1998. Antimicrobial and anticonvulsant activities of Viscum capense. J. Ethnopharmacol. 61, 237–241. https://doi.org/10.1016/S03788741(98)00054-3

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List of tables: Table 1 Chemical composition of Viscum L. species Group

Compounds

Viscum species

References

Misteltoe-specificcompounds album L., coloratum (Kom.) Nakai

Lectins

MLI, MLII, MLII, cbML1, cbML2, cbML3

Viscotoxins

A1, A2, A3, B, B2, 1-PS, U-PS, C1

Flavonoids

Other well-known compounds Rhamnetin, rhamnazin, 3-O-methylquercetin,

album L.

album L.

(Lyu et al., 2000; Ochocka and Piotrowski, 2002; Stoeva et al., 2001; Urech et al., 2006) (Hussain et al., 2013; Ochocka and Piotrowski, 2002; Orrù et al., 1997; Romagnoli et al., 2003; Schaller et al., 1998; Urech et al., 2006) (Pietrzak et

35

taxifolin Rhamnetin-3-O-rhamnoside, quercetin-3-O-β-Dglucopyranoside-(1→6)-α-L-arabinoside, apigenin-6,8-di-C-glucoside Rhamnazin-3,4'-di-O-glucoside (2R)-5,7-dimethoxyflavanone-4'-Ο-glucoside, (2S)-3',5,7-trimethoxyflavanone-4'-Ο-glucoside, 2'-hydroxy-3,4',6'-trimethoxychalcone-4-Οglucoside, 2'-hydroxy-4',6'-dimethoxychalcone-4-Οglucoside, 2'-hydroxy-4',6'-dimethoxychalcone-4Ο-[apiosyl (1→2)] glucoside Rhamnazin-3-O-β-D-glucoside, homoeriodictyol7-O-β-D-apiose (1→5)-β-D-apiose (1→2)-β-Dglycoside, pachypodol, 5,7,4'-trihydroxy-3,3'dimethoxyflavone Rhamnazin-3-O-β-D-glucoside, rhamnazin-3-O-β-D-(6''-β-hydroxy-βmethyglutaryl)-β-D-glucoside-4'-O-β-D-glucoside Isorhamnetin

coloratum (Kom.) Nakai

al., 2017) (Song et al., 2016)

coloratum (Kom.) Nakai album L.

(Fukunaga et al., 1989) (Fukunaga et al., 1987)

coloratum (Kom.) Nakai

Zhao et al., 2011)

coloratum (Kom.) Nakai

(Long et al., 2017)

album L., coloratum (Kom.) Nakai

Rhamnazin-3-O-β-D-apiosyl-(1→2)-β-D-[6''-(3hydroxy-3-methylglutaric methyl ester)]glucoside, rhamnazin-3-O-β-D-apiosyl-(1→2)-β-D-[6''-(3hydroxy-3-methylglutarate)]-glucoside, quercetin-3-O-β-D-glucoside Rhamnazin-4'-O-β-[apiosyl (1→2)]glucoside, (2S)-5-hydroxy-7,3'-dimethoxyflavanone-4'-O-β[apiosyl (1→2)]glucoside Rhamnazin-3-O-β-D-(6''-β-hydroxy-βmethyglutaryl)-glucoside, 5-hydroxy-3,7,3'-trimethoxyflavone-4'-O-β-Dglucoside Kaempherol

coloratum (Kom.) Nakai

(Lee et al., 2013; Pietrzak et al., 2017) (Li et al., 2012)

alni-formosanae Hayata

(Chou et al., 1999)

coloratum (Kom.) Nakai

(Long et al., 2017; Zhao et al., 2011)

album L.

Rhamnocitrin 3-O-apiosyl(1→5)apiosyl(1→2)[α-L-rhamnopyranosyl(1→6)]-β-Dglucopyranoside, pinocembrin 7-O-apiosyl(1→5)apiosyl(1→2)-βD-glucopyranoside isorhamnetin-3-O-β-D-glucoside

angulatum B.Heyne ex DC.

(Pietrzak et al., 2017; Vicas et al., 2011) (Lin et al., 2002)

Quercetin

album L., coloratum (Kom.) Nakai, ovalifolium DC.

coloratum (Kom.) Nakai

(Li et al., 2012; Zhao et al., 2011) (Khatun et al., 2016; Kumar et

36

7,3',4'-Trimethylquercetin Guercetin-3-O-α-L-rhamnoside, 3',4'-Odimethyltaxifolin, 3,5,7,4'-tetrahydroxy-3'methoxyflavanone 3,7,3'-tri-O-methylquercetin-4'-O-β-Dapiofuranosyl-(1→2)-O-β-D- glucopyranoside, 7,3'-di-O-methylquercetin-4'-O-β-Dglucopyranosyl-3-O-[6'''-(3-hydroxy-3methylglutaroyl)]-α-D-glucopyranoside, 7,3'-diO-methylquercetin-4'-O-β-D-glucopyranosyl-3O-[(6'''''→5'''')-O-1'''''-(sinap-4-yl)-β-Dglucopyranosyl-6'''-(3-hydroxy-3methylglutaroyl)]-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-Dglucopyranoside, (2S)-5-hydroxy-7,3'dimethoxyflavanone-4'-O-β-[apiofuranosyl (1→2)]-glucopyranoside Hyperoside

coloratum (Kom.) Nakai album L.

al., 2016; Lee et al., 2013; Lu et al., 2013; Pietrzak et al., 2017; Vicas et al., 2011) (Chen et al., 2009) (Li et al., 2011)

album L.

(Nhiem et al., 2013)

album L., coloratum (Kom.) Nakai

(Long et al., 2017; Trifunschi et al., 2017) (Trifunschi et al., 2017) (Leu et al., 2006; Li et al., 2015, 2012, 2011; Lin et al., 2002; Long et al., 2017; Zhao et al., 2011) (Fukunaga et al., 1989; Leu et al., 2006) (Li et al., 2012; Zhao et al., 2011) (Long et al.,

Isoquercitrin

album L.

Homoeriodictyol

album L.,angulatum B.Heyne ex DC., articulatum Burm. f..,coloratum (Kom.) Nakai

Homoeriodictyol-7-O-[apiosyl(1→2)]glucoside

coloratum (Kom.) Nakai

Homoeriodictyol-7-O-β-D-apiosyl-(1→2)-β-Dglucoside

coloratum (Kom.) Nakai

Homoeriodictyol-7-O-β -D-apiose-(1→2)-β-D-

coloratum (Kom.)

37

glucoside

Nakai

Homoeriodictyol-7-O-β-D-glucopyranoside-4'-Oβ-D-(5'''-cinnamoyl)apiofuranoside, homoeriodictyol-7-O-β-D-glucopyranoside-4'-Oβ-D-apiofuranoside, pinocembrin-7-O-β-Dapiofuranosyl(1→2)-β-D-glucopyranoside, pinocembrin-7-O-β-D-apiofuranosyl-(1→5)-β-Dapiofuranosyl-(1→2)-β-D-glucopyranoside, pinocembrin-7-O-cinnamoyl (1→5)-β-Dapiofuranosyl (1→2)]-β-D-glucopyranoside, 5,3',4'-trihydroxyflavanone-7-O-β-Dglucopyranoside, 4'-hydroxy-7,3'dimethoxyflavan-5-O-β-D-glucopyranoside Pinocembrin-7-O-β-D-glucopyranoside

articulatum Burm. f..

Homoeriodictyol-7-O-β-D-glucopyranoside

articulatum Burm. f..,

Homoeriodictyol-7-O-β-D-glucoside

articulatum Burm. f.., coloratum (Kom.) Nakai

(2S)-homoeriodictyol-7-O-glucoside, (2S)naringenin-7-O-glucoside, (2S)-pinocembrin-7-Oglucoside, (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-7O-glucoside, (2S)-5,7,3',4'-tetrahydroxyflavanone, (2S)-7,4'-dihydroxy-5,3'-dimethoxyflavanone Homoeriodictyol-7-O-β-D-apiosyl-(1→5)-β-Dapiosyl-(1→2)-β-D-glucoside

coloratum (Kom.) Nakai

(2S)-homoeriodictyol-7-O-β-D-apiofuranosyl(1→2)-O-β-D-glucopyranoside, (2S)-5-hydroxy7,3'-dimethoxyflavanone-4'-O-β-D-apiofuranosyl(1→2)-O-β-D-glucopyranoside Homoeriodictyol-7-O-β-apiosyl-(1→2)-O-βglucoside, homoeriodictyol-7-O-β-apiosyl-(1→5)-O-βapiosyl-(1→2)-O-β-glucoside Viscumneoside V

album L.

articulatum Burm. f..

coloratum (Kom.) Nakai

2017; Ma et al., 2015; Zhao et al., 2011) (Li et al., 2008)

(Kuo et al., 2010; Li et al., 2008) (Kuo et al., 2010; Li et al., 2011, 2008) (Li et al., 2015, 2012; Long et al., 2017; Ma et al., 2015; Zhao et al., 2011) (Leu et al., 2006)

(Li et al., 2012; Ma et al., 2015) (Thu et al., 2016)

coloratum (Kom.) Nakai

(Park et al., 2017)

album L.,angulatum B.Heyne ex DC.

(Lin et al., 2002; Nhiem et

38

Naringenin

album L., angulatum B.Heyne ex DC., articulatum Burm. f..,coloratum (Kom.) Nakai

Naringenin-7-O-β-D-glucopyranoside, eriodictyol-7-O-β-D-glucopyranoside, visartiside A, visartiside B, visartiside C Naringenin-7-O-β-D-glucoside, pinocembrin-7O-β-D-glucoside, eriodictyol-7-O-β-D-glucoside, 2R/2S-viscarticulide A, 2R/2S-viscarticulide B, 2R/2S-viscarticulide C Eriodictyol

articulatum Burm. f..

al., 2013) (Leu et al., 2006; Li et al., 2015, 2011; Lin et al., 2002; Pietrzak et al., 2017) (Kuo et al., 2010)

articulatum Burm. f..

(Li et al., 2015)

album L., articulatum Burm. f.., coloratum (Kom.) Nakai, liquidambaricola Hayata

(Li et al., 2015, 2011; Long et al., 2017; Pietrzak et al., 2017; Yang et al., 2005) (Kumar et al., 2016; Pietrzak et al., 2017) (Fukunaga et al., 1989; Long et al., 2017) (Fukunaga et al., 1989; Nhiem et al., 2013; Thu et al., 2016) (Lee et al., 2013; Pietrzak et al., 2017; Trifunschi et al., 2017) (Lu et al., 2013; Trifunschi et al., 2017; Tsyvunin et al., 2016) (Li et al., 2011, 2008) (Choudhary

Apigenin

album L.

Flavoyadorinin-B

coloratum (Kom.) Nakai

homo-flavoyadorinin-B

album L.,coloratum (Kom.) Nakai

Luteolin

album L., coloratum (Kom.) Nakai

Rutin

album L., ovalifolium DC.

5,4'-dihydroxyflavanone-7-O-β-Dglucopyranoside 5,7-dimethoxy-4'-hydroxy flavanone, 4',5-

album L., articulatum Burm. f.. album L.

39

dimethoxy-7-hydroxy flavanone, 4'-O-[β-Dapiosyl(1→2)]-β-D-glucosyl]-5-hydroxyl-7-Osinapylflavanone 5,7-dimethoxy-4'-O-β-Dglucopyranosideflavanone

album L.

5,7-dimethoxy-flavanone-4'-O-[β-Dapiofuranosyl(1→2)]-β-D-glucopyranoside

album L.

5,7-dimethoxy-flavanone-4'-O-[2''-O-(5'''-O-trans -cinnamoyl)-β-D-apiofuranosyl]-β-Dglucopyranoside, 2'-hydroxy-4',6'dimethoxychalcone-4-O-β-D-glucopyranoside, 2'hydroxy-4',6'-dimethoxychalcone- 4-O-[2''-O(5'''-O-trans -cinnamoyl)-β-D-apiofuranosyl]-β-Dglucopyranoside 5,7-dimethoxyflavanone-4'-O-[5'''-O-transcinnamoyl-β-D-apiofuranosyl]-β-Dglucopyranoside Sakuranetin

album L.

Isosakuranetin

album L.

Chrysin

coloratum (Kom.) Nakai,liquidambaricol a Hayata album L.

3'-Methoxyapiin

Phenolic acids

et al., 2010)

Gentisic acid, isochlorogenic acid, chlorogenic acid, neochlorogenic acid, coumaric acid, pcoumaric acid, m-coumaric acid, trans-mcoumaric acid, o-coumaric acid, sinapic acid, trans-cinnamic acid, cinnamic acid, gallic acid, digallic acid, p-hydroxybenzoic acid, protocatechuic acid, caffeic acid, syringic acid, isoferulic acid, ferulic acid, rosmarinic acid, veratric acid, vanillic acid, salicylic acid, ellagic acid

(Choudhary et al., 2010; Orhan et al., 2006, 2002) (Deliorman et al., 2000; Orhan et al., 2006, 2002) (Orhan et al., 2006, 2002)

album L.

(Orhan et al., 2014)

album L.

(Melo et al., 2018; Pietrzak et al., 2017) (Melo et al., 2018) (Long et al., 2017; Yang et al., 2005) (Nhiem et al., 2013; Thu et al., 2016) (Amer et al., 2013; Khatun et al., 2016; Lee et al., 2013; Leu et al., 2006; Long et al., 2017; Łuczkiewic z et al., 2001; Melo et al., 2018; Pietrzak et al., 2017; Trifunschi et al., 2017; Tsyvunin et

album L., coloratum (Kom.) Nakai, liquidambaricola Hayata

40

Sterols

Lignans

β-Sitosterol, γ-sitosterol

album L., coloratum (Kom.) Nakai, ovalifolium DC.

β-Sitosteryl-3-β-D-glucoside, stigmasteryl-3-β-Dglucoside Stigmasterol

coloratum (Kom.) Nakai album L., coloratum (Kom.) Nakai

Campesterol

album L.

Phytosterol, phytosterol-β-D-glucoside

album L.

Daucosterol

album L.

Alangilignoside C, (7R,8S,8'S)-4,9,4'-trihydroxy3,5,3',5'-tetramethoxy-7,9'-epoxylignan 9-O-β-Dglucopyranoside (ligalbumoside A) , (7S,8S,7'S,8'R)-4,9,4’-trihydroxy-3,5,3',5',7'pentamethoxy-7,9'-epoxylignan 9-O-β-Dglucopyranoside (ligalbumoside B), (7R,8R,7'S,8'S)-4,9,4'-trihydroxy-3,5,3',5',7'pentamethoxy-7,9'-epoxylignan 9-O-β-Dglucopyranoside (ligalbumoside C), (7S,8R,7'S,8'R)-4,9,4'-trihydroxy-3,5,3',5',7'pentamethoxy-7,9'-epoxylignan 9-O-β-Dglucopyranoside (ligalbumoside D), (7R,8S,7'R,8'S)-4,9,4',7'-tetrahydroxy-3,5,3',5'tetramethoxy-7,9'-epoxylignan 9-O-β-Dglucopyranoside(ligalbumoside E) Syringaresinol

album L.

album L., coloratum (Kom.) Nakai

(+)-Syringaresinal-4'-O-β-D-glucopyranoside, curuilignan D

album L.

(+)-Pinoresinol

album L., coloratum (Kom.) Nakai

al., 2016; Vicas et al., 2011; Yang et al., 2005) (Leu et al., 2006; Long et al., 2017; Lu et al., 2013; Urechet al., 2005; Vlad et al., 2016) (Leu et al., 2006) (Leu et al., 2006; Urech et al., 2005; Vlad et al., 2016) (Vlad et al., 2016) (Fukunaga et al., 1987) (Li et al., 2011) (Melo et al., 2018; Nhiem et al., 2012)

(Chen et al., 2009; Geetha et al., 2018; Li et al., 2011; Long et al., 2017) (Li et al., 2011) (Chen et al., 2009; Li et

41

(-)-Lyoniresinol 3α-O-β-D-glucopyranoside, (+)lyoniresinol 3α-O-β-D-glucopyranoside,

album L. album L., angulatum B.Heyne ex DC., articulatum Burm. f.., coloratum (Kom.) Nakai, ovalifolium DC.

Terpenoids

Betulinic acid

3-epi-Betulinic acid

coloratum (Kom.) Nakai album L., angulatum B.Heyne ex DC., articulatum Burm. f.., coloratum (Kom.) Nakai, liquidambaricola Hayata, ovalifolium DC.

Oleanolic acid

al., 2011; Nhiem et al., 2013) (Nhiem et al., 2013) (Delebinski et al., 2015; Fukunaga et al., 1987; Jadhav et al., 2010; Jadhav et al., 2010; Kim et al., 2015; Ko et al., 2016; Leu et al., 2006; Li et al., 2011; Lu et al., 2013; Nhiem et al., 2013; Urech et al., 2005; Vicas et al., 2011; WójciakKosior et al., 2016; Yang et al., 2009) (Chen et al., 2009; Yang et al., 2009) (Delebinski et al., 2015; Fukunaga et al., 1987; Jadhav et al., 2010; Jadhav et al., 2010; 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

epi-Oleanolic acid

coloratum (Kom.) Nakai album L., coloratum (Kom.) Nakai

Betulin

album L. Ursolic acid album L., ovalifolium DC. β-Amyrin

album L., coloratum (Kom.) Nakai

β-Amyrin acetate

album L., coloratum (Kom.) Nakai, ovalifolium DC. Lupeol

album L., ovalifolium DC. Lupeol acetate

Lupenyl acetate (3β)-Olean-12-ene-3,23-diol

album L. coloratum (Kom.)

al., 2013; Song et al., 2016; Urechet al., 2005; WójciakKosior et al., 2016; Yang et al., 2009, 2005) (Jung et al., 2004) (Ko et al., 2016; Li et al., 2011; Vlad et al., 2016) (Tsyvunin et al., 2016; Urech. et al., 2005) (Lu et al., 2013; Urech, et al., 2005; Vlad et al., 2016) (Fukunaga et al., 1987; Leu et al., 2006; Nhiem et al., 2013; Urech et al., 2005; Yang et al., 2009) (Leu et al., 2006; Li et al., 2011; Lu et al., 2013; Urech et al., 2005; Vlad et al., 2016) (Lu et al., 2013; Urech et al., 2005; Vlad et al., 2016) (Vlad et al., 2016) (Yang et al.,

43

Erythrodiol

Nakai album L., coloratum (Kom.) Nakai

coloratum (Kom.) Nakai Betulonic acid

Diarylheptanoid s

Phenylpropanoi d glycosides

α-Terpineol, carvone, trans-verbenol, cisverbenol, linalool, carvacrol, trans-carveol, borneol, 14-hydroxy-β-caryophyllene, geraniol, thymol, widdrol, verbenone, camphor, trans-βbergamotene (-)-Loliolide, vomifoliol, trans-α-bergamotene

album L.

Phytol,trans-phytol

album L., ovalifolium DC.

Loliolide

coloratum (Kom.) Nakai album L.

(3S,5R)-3-hydroxy-5-methoxy-1,7-bis(4hydroxyphenyl)-6E-heptene, (3S,5S)-3-hydroxy5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene, (3S)-3-hydroxy-1,7-bis(4-hydroxyphenyl)-6Ehepten-5-one 1,7-di-(p-hydroxyphenyl)-5-hydroxyl-cis-2,3epoxy-1-one 1,7-di-(3',4'-dihydroxyphenyl)-4-hepten-3-one

album L.

coloratum (Kom.) Nakai cruciatum Sieber ex Boiss.

Centrolobol, acerogenin G

album L.

Coniferin

album L.

Coniferylalcohol-4-O-β-D-apiofuranosyl (1→2)β-D-glucopyranoside, syringenin 4-O-β-D-apiofuranosyl (1→2)-β-Dglucopyranoside Kalopanaxin D

album L.

Syringin

album L., coloratum (Kom.) Nakai

album L.

2009) (Nhiem et al., 2013; Yang et al., 2009) (Chen et al., 2009; Long et al., 2017; Yang et al., 2009) (Kürkçüoǧl u et al., 2002)

(Ćebović et al., 2008) (Chen et al., 2013; Nhiem et al., 2013) (Chen et al., 2009) (Nhiem et al., 2013)

(Yao et al., 2007) (MartínCordero et al., 2001) (Li et al., 2011) (Deliorman et al., 2000, 1999; Orhan et al., 2002; Panossian et al., 1998) (Panossian et al., 1998)

(Deliorman et al., 2000, 1999; Orhan et al., 2002) (Deliorman et al., 2000, 1999;

44

Alkaloids

Carboxylic and fatty acids

Syringenin 4-O-glucoside, syringenin 4-Oapiosyl-glucoside Syringenin 4'-O-β-D-apiofuranosyl-(1→2)-β-OD-glucopyranoside Retamine, lupanine, 5,6-dehydrolupanine, cytosine, N-methylcytisine, ammodendrine

4,5,4'-trihydroxy-3,3'-iminodibenzoic acid, 4,5,4',5'-tetrahydroxy-3,3'-iminodibenzoic acid p-Hydroxyphenylacetic acid

album L. album L. cruciatum Sieber ex Boiss.

album L. articulatum Burm. f..

Hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid

album L.

Undecanoic acid, Z-7-hexadecenoic acid, cis-10nonadecenoic acid, cis-11-eicosenoic acid Oleic acid, linoleic acid, palmitic acid, stearic acid

album L.

Cerotic acid, lignoseric acid, behenic acid, arachidic acid, montanic acid

album L.

Monosaccharide

Arabinose, xylose, glucose, galactose, mannose

album L.

Polysaccharides

VCP1, VCP2, VCP3

Polyols

Xylitol, inositol

coloratum (Kom.) Nakai album L.

Other

1-O-benzyl-[5-O-benzoyl-β-Dapiofuranosyl(1→2)]-β-D-glucopyranoside 3-(4-acetoxy-3,5-dimethoxy)-phenyl-2Epropenyl-β-D-glucopyranoside, 3-(4-hydroxy-3,5-dimethoxy)-phenyl-2E-

album L.

articulatum Burm. f.. album L.

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) (Melo et al., 2018) (Nhiem et al., 2013) (MartínCordero et al., 1997; Martin Cordero et al., 1993) (Amer et al., 2012) (Li et al., 2015) (Kürkçüoǧl u et al., 2002) (Vlad et al., 2016) (Ćebović et al., 2008; Orhan and Orhan, 2006; Urech et al., 2005; Vlad et al., 2016) (Orhan and Orhan, 2006) (Arda et al., 2003) (Chai and Zhao, 2016) (Arda et al., 2003) (Li et al., 2008) (Choudhary et al., 2010)

45

propenyl-β-D-glucopyranoside 2',3',4',3''-tetramethoxy-1,3-diphenylpropane 5',4''-di-O-β-D-glucopyranoside 2,6-dimethylocta-2,7-diene-1,6-diol 6-O-[6’-O-βD-apiofuranosyl]-β-D-glucopyranoside 5,7-dihydroxychromone

5-hydroxychromone-7-O-glucoside, 4hydroxybenzaldehyde, syringaldehyde, methyl-3O-feruloylquinate, 4-O-cinnamoylquinic acid, vanillin, β-sitostenone, acetovanillone, 2,6dimethoxy-p-benzoquinone, 2-deoxy-epi-inositol, thymine, uracil 3-(3'-carbomethoxypropyl) gallic acid, 3-(3'carbomethoxypropyl)-7→3''protocatechoylgalloate Benzaldehyde, 3-methyl-1-butanal (isovaleraldehyde), phenylacetaldehyde, hexenal, heptanal, octanal, nonanal, (E)-2-decenal, (E)-2nonenal, (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)-2,4nonadienal, (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-2one, 3-nonen-2-one, trans-linalool-oxide (furanoid), 1-octen-3-ol, (E,E)-3,5-octadien-2one, tetramethylpyrazine, 3,5-octadien-2-one, 6methyl-3,5-heptadien-2-one, pinocarvone, nopinone, terpinen-4-ol, neoisomenthol, widdrene (thujopsene), myrtenal, pulegone, transpinocarveol, p-mentha-1,5-dien-8-ol, naphtalene, (E)-anethol, p-cymen-8-ol, benzylacetone, 1methyl naphthalene, methyl eugenol, trans-βionone-5,6-epoxide, (E)-geranyl acetone, γoctalactone, γ-nonalactone 5,7,8-trimethyl-2-chromanone, 4,4,5,8tetramethylchroman-2-ol, α-tocopherol, pentadecanal, 3-isopropenyl-2methylcyclohexanol, 1-heptatriacotanol, behenic alcohol, 2-cis-9-octadecenyloxyethanol, 2,4decadienal, 4-[2,6,6-trimethyl-5-cyclohexen-1yl)-2-butanone, 4-(2,3,6-trimethylphenyl)2butanone, 4-(2,4,4-trimethyl-cyclohexa-1,5dienyl) but-3-en-2-one, 2-methyl-4-(2,6,6trimethylcyclohex-1-enyl) but-2-en-1-ol, 1-(2,6,6-

angulatum B.Heyne ex DC. album L. album L., coloratum (Kom.) Nakai coloratum (Kom.) Nakai

(Lin et al., 2002) (Deliorman et al., 2001) (Leu et al., 2006; Li et al., 2011) (Leu et al., 2006)

album L.

(Amer et al., 2013)

album L.

(Kürkçüoǧl u et al., 2002)

album L.

(Vlad et al., 2016)

46

trimethyl-cyclohex-1-enyl_-butane-1,3-dione, 4,4,5,6,8-pentamethyl-3,4-2H-coumarin, 1,1,4atrimethyl-3,4,4a,5,6,7-hexahydro-2(1H)naphthalenone, 1,1,6-trimethyl-1,2dihydronaphthalene, 3,3-dimethyl-1,2,3,4tetrahydro-1,2-naphthalenediol, 2,5,8-trimethyl1,2-dihydronaphthalene, 1,2-naphthalene diol, 3', 8, 8'-trimethoxy-3-piperidin-1-yl-2,2'-binaphthyl1,1,4,4’-tetrone, syringol, cendran-8,13-diol, 1,2,4-cyclopentanetrione, (-)-calamenene, 4,47atrimethyl-5,6,7,7a-tetrahydro-1-benzofuran2(4H)-one, 16-heptadecen-2,5,8-trione, 3,3,5,6tetramethyl-1-indanone, 3-oxo-7,8-dihydro-αionol, 8,9-dehydro-neoisolongifolene, Z-9pentadecenol, pentadecanoic acid, 14-methyl, methyl ester, pentadecanoic acid 13-methyl methyl ester, (2E)-3,7,11,15-tetramethyl-2hexadecen-1-ol, i-propyl-9-hexadecenoate, 9tetradecenoic acid trimethylsilyl ester, palmitic anhydride, 3-deoxyestradiol, α-glycerol linolenate, methyl 5,11,14-eicostrienoate, 6,9,12,15-docosatetraenoic acid methyl ester, 17pentatriacontene, 4,4,6a,6b,8a,11,14b-octamethyl1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b octadecahydro-2H-picen-3-one, (3E,5E)-7isopropyl-8-methyl-3,5,7-nonatrien-2-one, cedr-8en-13-ol, L-celemene, 2,2,3,3-tetramethyl-1indanone, methyl-4-(3-hydroxy-3-methyl-1butynyl) benzoate, azulol, 1,3dimethylpyrido[3,2-d]pyrimidine-2,4-(1H,3H)dione, 7,8-dehydro-8a-hydroxy isolongifolene, myristic acid anhydride, E-2-methyl-3-tetradecen1-ol acetate, cis-10-heptadecenoic acid methyl ester, 2,3-dihydroxypropyl elaidate, 2-tert-butyl6-[(3-tert-butyl-2-hydroxy-5methylphenyl)methyl]-4-methyl-phenol, 17pentatriacontene, 5-(7a-isopropenyl-4,5-dimethyloctahydroinden-4-yl)-3-methyl-pent-2-enal, lanosterol, δ7-chondrillastenol Benzeneacetaldehyde, hexacosane, undecane, (E)2-hexenal, 1-octanol, chlorobenzene, 1,3dichloro-benzene, dihydroedulan II (cis), 6,8nonadien-2-one, 6-methyl-5-(1methylethylidene)-, trans-β-damascenone, 2(acetylmethyl)-(+)-3-carene, transgeranylacetone, 3,5-di-tert-butylphenol, 9octadecyne, phytone, phthalic acid, isobutyl isoporpyl ester, dibutyl phthalate, furfurol n-Tricosane, n-tetracosane, n-pentacosane, nhexacosane, n-heptacosane, n-octacosane, nnonacosane (celidoniol), n-triacontane, γ-

ovalifolium DC.

(Chen et al., 2013)

album L.

(Ćebović et al., 2008)

47

tocopherol (vitamin E), 1H-2-benzopyrane-1on,3,4-dihydro-8-hydroxy-3-methyl-(CAS) isocoumarine, 2(4H)-benzofuranone-5,6,7,7atetrahydro-4,4,7a-trimethyl-(R) aktinidiolid, 2-pentadecanone-6,10,14-trimethyl-(CAS) hexahydrofarnesyl acetone, trans-β-farnesene, fytol, 9-tricosene,(Z)-(CAS), muscalure, 4,8,12trimethyltridecane-4-olid, ergosta-5,7,22-trien-3ol Liquidamboside

Phenylalanine, astragaloside IV, isornetin-3-O-Dglucoside, coumarin (+)-Medioresinol, nerolidol

coloratum (Kom.) Nakai, liquidambaricola Hayata coloratum (Kom.) Nakai album L.

Viscolin

coloratum (Kom.) Nakai

Hentriacontanol

articulatum Burm. f..

Hexahydrofarnesyl acetone

album L.

β-Ionone

album L., ovalifolium DC.

1-Octadecene, ethyl palmitate, 28-hydrxyamyrone, β-amyrinpalmitate Adenosine, thymidine, syringing, 1,5-dimethyl6,8-dioxatricyclo[4.2.1.03,9]nonane-3-methyl-2,4pentadienoic acid Visartiside D, visartiside E, visartiside F, (4'hydroxy-2',3',6',3''-tetramethoxy-1,3diphenylpropane)-4''-O-β-D-glucopyranoside

ovalifolium DC. coloratum (Kom.) Nakai articulatum Burm. f..

(Long et al., 2017; Yang et al., 2005) (Long et al., 2017) (Nhiem et al., 2013) (Leu et al., 2006; Liang et al., 2011) (Geetha et al., 2018) (Kürkçüoǧl u et al., 2002; Vlad et al., 2016) (Chen et al., 2013; Kürkçüoǧlu et al., 2002) (Lu et al., 2013) (Park et al., 2017) (Kuo et al., 2010)

48