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Sideritis scardica extracts inhibit aggregation and toxicity of amyloid- β in Caenorhabditis elegans used as a model for Alzheimer’s disease

  • April 2018
  • PeerJ 6(4):e4683
DOI:10.7717/peerj.4683
Authors:
Felix Heiner at Finzelberg GmbH & Co. KG
Felix Heiner
  • Finzelberg GmbH & Co. KG
Bjoern Feistel at Finzelberg GmbH & Co KG
Bjoern Feistel
  • Finzelberg GmbH & Co KG
Michael Wink at Universität Heidelberg
Michael Wink
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Abstract and Figures

Background Beyond its traditional uses in the Balkan area, Sideritis scardica (known as Greek mountain tea, Lamiaceae) is currently extensively investigated for its pharmacological activity in the central nervous system. Antidepressant, psychostimulating, cognition-enhancing and neuroprotective properties have been described. In this study, we tested hydroalcoholic extracts of S. scardica for their potential to counteract amyloid-β toxicity and aggregation, which plays a crucial role in the pathogenesis of Alzheimer’s disease. Methods For this purpose, we have chosen the nematode Caenorhabditis elegans , which is used as a model organism for neurodegenerative diseases. The concentration of different polyphenols in extracts prepared from water, 20, 40, 50, and 70% ethanol was analysed by HPLC. Additionally, polar and unpolar fractions were prepared from the 40% ethanolic extract and phytochemically analysed. Results Essentially, the contents of all measured constituents increased with the lipophilicity of the extraction solvents. Treatment of transgenic C. elegans strains expressing amyloid-β with the extracts resulted in a reduced number of peptide aggregates in the head region of the worms and alleviated toxicity of amyloid-β, observable through the degree of paralysed animals. The mid-polar extracts (40 and 50% ethanol) turned out be the most active, decreasing the plaque number by 21% and delaying the amyloid-β-induced paralysis by up to 3.5 h. The more lipophilic extract fractions exhibited higher activity than the hydrophilic ones. Discussion Sideritis scardica extracts demonstrated pharmacological activity against characteristics of Alzheimer’s disease also in C. elegans , supporting current efforts to assess its potential for the treatment of cognitive decline. The active principle as well as the mode of action needs to be investigated in more detail.
Exemplary chromatogram of 20% ethanolic S. scardica extract. Caffeoylquinic acids (calculated as chlorogenic acid), acteoside, and flavonoids (calculated as scutellarin) could be quantified by HPLC with UV detection at 330 nm. Full-size DOI: 10.7717/peerj.4683/fig-1
Exemplary chromatogram of 20% ethanolic S. scardica extract. Caffeoylquinic acids (calculated as chlorogenic acid), acteoside, and flavonoids (calculated as scutellarin) could be quantified by HPLC with UV detection at 330 nm. Full-size DOI: 10.7717/peerj.4683/fig-1
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Flowchart and phytochemical analysis of the fractions prepared from 40% ethanolic S. scardica extract. Percentage distribution of mass is given for each pair of fractionation type in the flowchart above. Occurring differences to 100% are loss of preparative handling. Full-size DOI: 10.7717/peerj.4683/fig-2
Flowchart and phytochemical analysis of the fractions prepared from 40% ethanolic S. scardica extract. Percentage distribution of mass is given for each pair of fractionation type in the flowchart above. Occurring differences to 100% are loss of preparative handling. Full-size DOI: 10.7717/peerj.4683/fig-2
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Thin layer chromatogram of polar constituents of 40% ethanolic S. scardica extract and its fractions after spraying with anisaldehyde solution R. Allocation of the tracks: primary extract with 40% ethanol (1); butanolic (2) and aqueous (3) phase of liquid-liquid extraction; supernatant (4) and precipitated fraction (5) of reprecipitation in 70% ethanol; ethanolic (6) and aqueous (7) phase of resin separation. Full-size DOI: 10.7717/peerj.4683/fig-3
Thin layer chromatogram of polar constituents of 40% ethanolic S. scardica extract and its fractions after spraying with anisaldehyde solution R. Allocation of the tracks: primary extract with 40% ethanol (1); butanolic (2) and aqueous (3) phase of liquid-liquid extraction; supernatant (4) and precipitated fraction (5) of reprecipitation in 70% ethanol; ethanolic (6) and aqueous (7) phase of resin separation. Full-size DOI: 10.7717/peerj.4683/fig-3
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Effect of Sideritis scardica on Aβ aggregation in C. elegans. (A) Fluorescence microscopic image of the head region of a worm from strain CL2006. Arrowheads point out the β-amyloid plaques that were stained with thioflavin S. (B, C, D) Reduction in number of the Aβ aggregates. All extracts were tested in a concentration of 600 µg/mL compared to 100 µg/mL EGCG as a positive control (B); the 20% and 50% ethanolic extract were tested in additional concentrations to show dose-dependence (C). All fractions were tested in a concentration of 400 µg/mL compared to the original 40% ethanolic extract in the same concentration (D). Controls were treated with 0.5% ethanol. *p < 0.05; ***p < 0.001; concentrations in µg/mL. Full-size DOI: 10.7717/peerj.4683/fig-4
Effect of Sideritis scardica on Aβ aggregation in C. elegans. (A) Fluorescence microscopic image of the head region of a worm from strain CL2006. Arrowheads point out the β-amyloid plaques that were stained with thioflavin S. (B, C, D) Reduction in number of the Aβ aggregates. All extracts were tested in a concentration of 600 µg/mL compared to 100 µg/mL EGCG as a positive control (B); the 20% and 50% ethanolic extract were tested in additional concentrations to show dose-dependence (C). All fractions were tested in a concentration of 400 µg/mL compared to the original 40% ethanolic extract in the same concentration (D). Controls were treated with 0.5% ethanol. *p < 0.05; ***p < 0.001; concentrations in µg/mL. Full-size DOI: 10.7717/peerj.4683/fig-4
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nfluence of S. scardica on Aβ-induced paralysis. (A, B) Paralysis curves from the first set of experiments. Compared to the control (0.5% ethanol) CL4176 worms treated with 600 µg/mL extract prepared from water, 20, 50, and 70% ethanol were paralysing slower and to a lesser extent (A). The control strain, which is not expressing Aβ, did not show any paralysis. Amongst(continued on next page.. . ) Full-size DOI: 10.7717/peerj.4683/fig-5
nfluence of S. scardica on Aβ-induced paralysis. (A, B) Paralysis curves from the first set of experiments. Compared to the control (0.5% ethanol) CL4176 worms treated with 600 µg/mL extract prepared from water, 20, 50, and 70% ethanol were paralysing slower and to a lesser extent (A). The control strain, which is not expressing Aβ, did not show any paralysis. Amongst(continued on next page.. . ) Full-size DOI: 10.7717/peerj.4683/fig-5
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Sideritis scardica extracts inhibit aggregation and toxicity of amyloid- β in Caenorhabditis elegans used as a model for Alzheimer’s disea
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Supplementary resources (6)

Supplemental Information 2
Data
April 2018
Felix Heiner · Bjoern Feistel · Michael Wink
Supplemental Information 3
Data
April 2018
Felix Heiner · Bjoern Feistel · Michael Wink
Data S2
Data
April 2018
Felix Heiner · Bjoern Feistel · Michael Wink
Data S1
Data
April 2018
Felix Heiner · Bjoern Feistel · Michael Wink
Supplemental Information 1
Data
April 2018
Felix Heiner · Bjoern Feistel · Michael Wink
Figure S1
Data
April 2018
Felix Heiner · Bjoern Feistel · Michael Wink
... Four of the eight studied SS mixtures demonstrated a statistically important neuroprotective capacity against the cytotoxicity caused by amyloid beta peptides, further confirming the potential of SS to provide mixtures or constituents that can be beneficial to patients with AD. Previous studies have shown that methanolic, ethanolic, and aqueous SS extracts, as well as ethanolic partitions, can reduce Aβ 1-42 aggregation and stop neuronal loss in cell lines and mouse and worm models of AD [36][37][38]. Specifically, in mice, SS extracts have been shown to decrease soluble Aβ 1-42 and Aβ aggregation by enhancing the phagocytic microglia response of Aβ and inducing the expression of a-secretase ADAM10, which cleaves Aβ [36]. Here, we show that four SS extracts (SSDM, SSM, SSW1, and SSDE) can also reduce the cytotoxic activity of Aβ [25][26][27][28][29][30][31][32][33][34][35] , with SSW1 showing this potential in differentiated cells as well. ...
... In addition, for the first time, we present neuroprotectivity in SS extracts generated by using less-polar solvents, such as dichloromethane. Nevertheless, the more polar extracts, such as the methanolic and aqueous extracts, are the strongest in terms of neuroprotectivity, as also indicated by previous findings [36][37][38][39]. The presence of known neuroprotective SS compounds (Tables 1 and 2), such as luteolin, apigenin, ferulic acid, chlorogenic acid, caffeic acid, ellagic acid, myricetin, quercetin, protocatechuic acid, gallic acid, vanillic acid, syringic acid, p-coumaric acid, kaempferol, verbascoside, and forsythoside A, likely confers Aβ [25][26][27][28][29][30][31][32][33][34][35] anti-neurotoxicity to the four neuroprotective fractions presented here [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98]. ...
Sideritis scardica Extracts Demonstrate Neuroprotective Activity against Aβ25–35 Toxicity
Article
Full-text available
  • Apr 2023
Alzheimer’s disease (AD) is the most prevalent neurodegenerative condition, primarily affecting seniors. Despite the significant time and money spent over the past few decades, no therapy has been developed yet. In recent years, the research has focused on ameliorating the cytotoxic amyloid beta (Aβ) peptide aggregates and the increased elevated oxidative stress, two interconnected main AD hallmarks. Medicinal plants constitute a large pool for identifying bioactive compounds or mixtures with a therapeutic effect. Sideritis scardica (SS) has been previously characterized as neuroprotective toward AD. We investigated this ability of SS by generating eight distinct solvent fractions, which were chemically characterized and assessed for their antioxidant and neuroprotective potential. The majority of the fractions were rich in phenolics and flavonoids, and all except one showed significant antioxidant activity. Additionally, four SS extracts partly rescued the viability in Aβ25–35-treated SH-SY5Y human neuroblastoma cells, with the initial aqueous extract being the most potent and demonstrating similar activity in retinoic-acid-differentiated cells as well. These extracts were rich in neuroprotective substances, such as apigenin, myricetin-3-galactoside, and ellagic acid. Our findings indicate that specific SS mixtures can benefit the pharmaceutical industry to develop herbal drugs and functional food products that may alleviate AD.
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... Likewise, infused beverages such as different tea (Camelia sinenesis (L.) Kuntze) varieties [106], coffee (Coffea arabica L.) [107], Greek mountain tea (Sideritis scardica Griseb.) [108], rock tea (Jasonia glutinosa (L.) DC.) [109], and yerba mate (Ilex paraguariensis A.St.-Hil.) [110] were also tested. ...
... All the products that prevented or reduced phenotypic changes in the transgenic models also decreased deposits or plaques of Aβ, at least in the studies where they were measured. Extracts of Kushui rose [121], Greek mountain tea [108], Chinese liquorice [97], and the leaves of coconut [124], G. biloba [99] and G. uralensis [97] reduced Aβ deposits in the CL2006 strain. A similar effect was reported for several compounds isolated from G. uralensis extract including glycyrrhetinic acid, isoliquiritigenin, glycyrrhizic acid and its aglycon [97], as well as ferulic acid [146], otophylloside B [138] and oleuropein aglycone [135]. ...
Natural Bioactive Products and Alzheimer’s Disease Pathology: Lessons from Caenorhabditis elegans Transgenic Models
Article
Full-text available
  • May 2022
Alzheimer’s disease (AD) is an age-dependent, progressive disorder affecting millions of people. Currently, the therapeutics for AD only treat the symptoms. Although they have been used to discover new products of interest for this disease, mammalian models used to investigate the molecular determinants of this disease are often prohibitively expensive, time-consuming and very complex. On the other hand, cell cultures lack the organism complexity involved in AD. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for the investigation of the pathophysiology of human AD. Numerous models of both Tau- and Aβ-induced toxicity, the two prime components observed to correlate with AD pathology and the ease of performing RNA interference for any gene in the C. elegans genome, allow for the identification of multiple therapeutic targets. The effects of many natural products in main AD hallmarks using these models suggest promising health-promoting effects. However, the way in which they exert such effects is not entirely clear. One of the reasons is that various possible therapeutic targets have not been evaluated in many studies. The present review aims to explore shared therapeutical targets and the potential of each of them for AD treatment or prevention.
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... In previous studies, two Greek species, namely S. scardica and Sideritis euboea Heldr. have been evaluated for neuroprotective activity and cognitive improvement [10][11][12][13]. These pharmacological activities for the herbal preparation of S. scardica have also been studied in a clinical trial showing that Sideritis improved picture recognition, speed of attention, and lowered state of anxiety [14]. ...
Metabolic Fingerprinting of Different Sideritis Taxa Infusions and Their Neurogenic Activity
Article
  • Apr 2023
Over the last years, Sideritis extracts were shown to improve memory. However, their potential to promote the generation of new neurons, starting with the neuronal differentiation of neural stem cells, remains unexplored. Therefore, the present study aimed to evaluate the neurogenic effects of different Sideritis infusions in neural stem and precursor cells and their impacts on cell viability. Moreover, the metabolic fingerprints were recorded using LC-DAD, LC-ESIHRMS, and GC-MS. The neurogenic potential from infusions of the eight Sideritis taxa tested was as potent as the classical neuronal inducer combination of retinoic acid and valproic acid. Further cytotoxicity assays revealed that the IC50 values of extracts were comprised between 163 µg/mL and 322 µg/mL. Hierarchical cluster analyses of the metabolic fingerprints unveiled, that the two Sideritis taxa with the lowest IC50 values were the most divergent in the analytical techniques used. As the analysis focused on polyphenols, it is reasonable to assume that these compounds are responsible for the effect on the cell viability of SH-SY5Y neuroblastoma cells. This study is the first report on the neurogenic potential of Sideritis taxa and might support the use of Sideritis herbal preparations in the context of neurodegenerative diseases.
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... The possibility of S. scardica treatment being a potent and well-tolerated option for treatment of AD in human was also discussed in some research work. Hydroethanolic S. scardica extracts inhibit A␤ aggregation and toxicity in Caenorhabditis elegans, used as a model for AD, with phenylethanoid glycoside as a potentially active substance in the extract [47]. In AD ␤-amyloidosis mouse models and aged C57Bl/6 mice, cognitive enhancement and A␤-counteracting effects were also observed after daily oral treatment with Sideritis euboea and S. scardica extracts [48]. ...
Effects of Sideritis scardica Extract on Scopolamine-Induced Learning and Memory Impairment in Mice
Article
Background: The neurodegenerative process in Alzheimer's disease, one of the most common types of dementia worldwide, mostly affects the cholinergic neurotransmitter system and, to a lesser extent, the monoaminergic one. The antioxidant acetylcholinesterase (AChE) and triple monoamine reuptake inhibitory activity of Sideritis scardica (S. scardica) and other Sideritis species has already been reported. Objective: To investigate the effects of S. scardica water extracts on the learning and memory processes, anxiety-like behavior, and locomotor activities in scopolamine (Sco)-induced dementia in mice. Methods: Male Albino IRC mice were used. The plant extract was administered for 11 consecutive days in the presence or absence of Sco (1 mg/kg, i.p). The behavioural performance of the animals was evaluated by passive avoidance, T-maze, and hole-board tests. The effects of extract on AChE activity, brain noradrenalin (NA), and serotonin (Sero) content, and antioxidant status were also monitored. Results: Our experimental data revealed that the S. scardica water extract caused a reduction in degree of memory impairment and anxiety-like behaviour in mice with scopolamine-induced dementia. The extract did not affect changed by the Sco AChE activity but impact reduced brain NA and Sero levels and demonstrated moderate antioxidant activity. In healthy mice we did not confirm the presence of anxiolytic-like and AChE inhibitory effects of the S. scardica water extract. The extract did not change the control Sero brain levels and reduce those of NA. Conclusion: S. scardica water extract demonstrated memory preserving effect in mice with scopolamine-induced dementia and deserve further attention.
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... In an in vivo Alzheimer mice model, extracts of Sideritis spp have shown to reduce intracerebral levels of Aβ and improve cognitive functions (Hofrichter et al., 2016). Previously, S. scardica extracts has been shown to inhibit aggregation and toxicity of amyloid-β in the nematode Caenorhabditis elegans used as a model for Alzheimer's disease (Heiner et al., 2018). Hence, it is of interest to evaluate the nootropic properties of compounds isolated from S. scardica acting as inhibitors of AChE and BuChE. ...
Immunomodulating polyphenols from Sideritis scardica
Article
  • Sep 2022
The herb Sideritis scardica is used in traditional medicine in the Balkan Peninsula. Limited information exists on its health effects, such as improvement of cognitive functions. This study explores the in vitro anti-inflammatory effects of extracts and polyphenols of S. scardica with focus on neurodegenerative disease. BuOH, DCM and EtOAc fractions were isolated from the crude EtOH extract of aerial parts of S. scardica and further purified by chromatographic methods. Eleven phenolic compounds were isolated. The extracts and compounds were assessed for immunomodulatory, enzyme-interacting and cytotoxic properties. The crude extract, EtOAc fraction and precipitate, BuOH fraction, verbascoside and acetylallosylglucosyl-isoscutellarein 4′-methylether displayed DPPH scavenging activity. The EtOAc fraction and echinaticin displayed XO inhibiting activity. The DCM fraction reduced nitric oxide production in D2SC/1 dendritic cells and demonstrated potent activity in a human complement assay. Verbascoside and chlorogenic acid lowered NO levels without affecting cell viability in D2SC/1 dendritic cells. The results reveal a broad-spectrum activity of this herb, which might potentially serve as a multi-target system in Alzheimer’s disease.
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Kombucha Fermentation of Olympus Mountain Tea (Sideritis scardica) Sweetened with Thyme Honey: Physicochemical Analysis and Evaluation of Functional Properties
Article
Full-text available
  • Sep 2023
This study implemented kombucha fermentation of Olympus Mountain tea (Sideritis scardica) sweetened with honey (OMTWH) in order to investigate the potential for producing a novel beverage with functional properties. The increase in the total count of bacteria and yeast suggests that the OMTWH acts as a viable substrate for supporting the proliferation of the microorganisms of the Kombucha symbiotic culture. The fermentation resulted in a reduction in pH and increased total titratable acidity. After fermentation, a statistically significant increase in the vitamins C, B1, B2, B6, B7, and B12 content was observed (p < 0.05). Total phenolics and antioxidant activity of the fermented beverage was significantly enhanced, as assessed by the method of Folin–Ciocalteu and ABTS assay, respectively. Results revealed that OMTWH had a potent inhibitory activity of α-amylase, α-glucosidase, acetylcholinesterase, and butyrylcholinesterase; OMTWH fermented with a kombucha consortium exhibited even higher inhibition. Hence, the process of kombucha fermentation can convert OMTWH into a novel beverage with enhanced functional properties.
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Plant Growth Regulators and Activated Charcoal Selectively Affect Phenylethanoid and Flavone Glycoside Accumulation in Sideritis scardica Griseb. Tissue Culture
Article
Full-text available
  • Jul 2023
Sideritis scardica Griseb. is a Balkan endemic species traditionally used for the treatment of pulmonary emphysema and angina pectoris. Recent research has also shown its phytotherapeutic potential as an anticancer and neuroprotective agent. These findings, as well as the endangered status of the species in its wild habitats, have motivated the present research on application of plant cell tissue and organ culture for the purposes of both valuable germplasm conservation and secondary metabolites production. Shoot cultures of the plant were initiated from sterile germinated seeds and the effects of activated charcoal (AC), as well benzyl adenine and 1-naphthaleneacetic acid treatments, were experimented. The phenolic profile analysis was performed by HPLC/DAD/MSn. Comparison with samples collected from wild plants in their natural habitat was performed. It was established that in vitro multiplication induced by plant growth regulators (PGRs) was accompanied by a higher impairment of leaf morphology and trichome formation, as well as by the occurrence of plantlet hyperhydricity and callus formation, as compared with the AC treatments. Shoot culture-derived plant material was shown to produce two phenylethanoids and five flavone glycosides, not detected in the wild collected plant material. In addition, the two types of in vitro culture treatments led to the stimulation of either flavone glycosides or phenylethanoids in the in vitro cultivated plants. Thus, AC stimulated, to a higher extent, flavone glycosides’ accumulation, leading to an elevated flavone/phenylethanoid ratio, as compared with PGR treatments.
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Omics approaches to investigate the neuroprotective capacity of a Citrus sinensis (sweet orange) extract in a Caenorhabditis elegans Alzheimer’s model
Article
Citrus sinensis by-products are a promising source of neuroprotective molecules. In this study, a pressurized liquid extract of Citrus by-products (PLE100) has been extensively characterized, and its neuroprotective capacity tested in the Caenorhabditis elegans strain CL4176, a validated in vivo model of Alzheimer's disease (AD). More than 450 compounds have been annotated in the extract, being triacylglycerols (TGs), stigmastanes, fatty acids (FAs) and carbohydrates the most abundant. The results demonstrate that worms PLE100-treated are significantly protected in a dose-dependent manner against the Aβ-peptide paralysis toxicity. The RNA-Seq data showed an alteration of 294 genes mainly related to the stress response defense along with genes involved in the lipid transport and metabolism. Moreover, the comprehensive metabolomics study allowed the identification of 818 intracellular metabolites, of which 54 were significantly altered (mainly lipids). The integration of these and previous results provides with new evidences of the protection mechanisms of this promising extract.
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Amyloid β- but not Tau-induced neurotoxicity is suppressed by Manuka honey via HSP-16.2 and SKN-1/NRF2 pathways in an in vivo model of Alzheimer disease.
Article
Full-text available
  • Oct 2022
Alzheimer's is a chronic degenerative disease of the central nervous system considered the leading cause of dementia in the world. It is characterized by two etiopathological events related to oxidative stress: the aggregation of β-amyloid peptide and the formation of neurofibrillary tangles of hyperphosphorylated Tau protein in the brain. The incidence of this disease increases with age and has been associated with inadequate lifestyles. Some natural compounds have been shown to improve the hallmarks of the disease. However, despite its potential, there is no scientific evidence about Manuka honey (MH) in this regard. In the present work we evaluated the effect of MH on the toxicity induced by Aβ aggregation and Tau in a Caenorhabditis elegans model. Our results demonstrated that MH was able to improve indicators of oxidative stress and delayed Aβ-induced paralysis in the AD model CL4176 through HSP-16.2 and SKN-1/NRF2 pathways. Nevertheless, its sugar content impaired the indicators of locomotion (an indicator of tau neurotoxicity) in both the transgenic strain BR5706 and in the wild-type N2 worms.
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Ex Vivo Characterization of the Action of Sideritis Extract Using Electrical Activity in the Rat Hippocampus Slice Preparation
Article
Full-text available
  • Jan 2016
A hydroethanolic extract (20% V/V) from Herba Sideritis scardica has been recognized to positively influence cognition. The present investigation aimed at the question if this extract would be able to modify intra-hippocampal communication after oral administration of 100 mg/kg daily for one week. The glutamatergic synapse between Schaffer Collaterals and pyramidal cells can be tested by electric stimulation using single pulses or theta burst stimulation. The resulting population spike is modulated by compounds acting at the central nervous system or other preparations directly or as ex vivo approach. In this case the effect of the special extract was tested in vitro the next day after repetitive in vitro administration. Conventional recording technique in the in vitro hippocampus slice revealed an increase of the population spike in the presence of single stimuli and theta burst stimuli resulting in increased long-term potentiation. This effect was tried to modulate by several glutamate receptor antagonists, among them compounds targeting at the ionic NMDA receptor (CGS19755), AMPA receptor (NBQX), Kainate receptor (UBP301) and targeting at three metabotropic glutamate receptors (mGluR I (YM298198), mGluRII ((RS)-APICA)) and mGluRIII (MSOP). Only NBQX was able to prevent the action of the Sideritis scardica extract. Since the AMPA receptor has been related to cognition in several reports in the literature, it is concluded from this result that the positive action of Sideritis scardica extract on brain function involves a modulation of AMPA receptor dependent neurotransmission.
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Psychophysiological Effects of a Combination of Sideritis and Bacopa Extract (memoLoges<sup>®</sup>) in 32 Subjects Suffering from Mild Cognitive Impairment. A Double-Blind, Randomized, Placebo-Controlled, 2-Armed Study with Parallel Design
Article
Full-text available
  • Jan 2016
Mild cognitive impairment (MCI) can be regarded as a non-demented transitional stage during the development of Alzheimer’s disease. Early recognition of this stage might increase the chance of prevention by early treatment. Within a pilot study, two plant-derived preparations and mixtures thereof were tested successfully in subjects suffering from MCI. A combination of Sideritis scardica and Bacopa monnieri extract (memoLoges®) was chosen now for a repetitive dosing during 4 weeks. Thirty-two subjects aged 50 to 80 years and suffering from MCI (having a DemTect questionnaire score between 8 and 13) were recruited for intake of 2 capsules of the preparation per day. Quantitative EEG recording during relaxation and concomitant performance of three 5 minutes lasting psychometric tests (d2-concentration test, arithmetic calculation test and memory test) was achieved at the first day and one day after the last repetitive intake. Seventeen channels of EEG and one channel EOG (for artefact rejection) were recorded. After frequency analysis (FFT) current source density was calculated as reported earlier. One, two and three hours after intake of the herbal extract or placebo the whole procedure was repeated. Brain imaging was achieved by conversion of numerical values of spectral EEG power into spectral colors and additive color mixture according to RGB as used in TV settings. Intake of memoLoges® induced a trend of improvement of performance in psychometric testing (all three tests). During relaxation quantitative assessment of EEG data revealed attenuation of delta and theta spectral power in frontal brain as likewise reported in the presence of the Alzheimer drug rivastigmine, bringing the spectrum back to “normality”. During mental work memoLoges® induced statistically significant increases of beta power. Since MCI subjects produce less beta power in comparison to healthy subjects, this increase must likewise be seen as a positive effect pointing to a healthier spectrum.
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Sideritis spp. Extracts Enhance Memory and Learning in Alzheimer's β-Amyloidosis Mouse Models and Aged C57Bl/6 Mice
Article
Full-text available
Nowadays, Alzheimer's disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard to their effects on cognition in APP-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aβ deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in APP-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aβ42 load in APP-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α-secretase ADAM10. Moreover, the treatment was able to fully rescue neuronal loss of APP-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer's disease by affecting its most prominent hallmarks: Aβ pathology and cognitive decline.
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Psychophysiological Effects of Sideritis and Bacopa Extract and Three Combinations Thereof—A Quantitative EEG Study in Subjects Suffering from Mild Cognitive Impairment (MCI)
Article
Full-text available
  • Jan 2016
Mild cognitive impairment (MCI) is regarded as a transitional stage during the development of Alzheimer’s disease. Diagnosis of MCI can be obtained by the questionnaire “DemTect” in German speaking countries. Quantitative assessment has been successfully performed using psychometric testing concomitantly with quantitative EEG recording. The present investigation aimed at the possible treatment of MCI with two botanicals, namely extracts from Sideritis scardica (500 mg) or Bacopa monnieri (320 mg) and three combinations thereof using this method in order to find a new treatment. The performance of the d2-test, an arithmetic calculation test (CPT) and a memory-test revealed better performance for the d2-test only in the presence of Sideritis extract or the combinations with Bacopa extract. Quantitative EEG assessment during the different experimental conditions showed massive differences between both extracts. Whereas Sideritis extract and its combination with a low amount of Bacopa extract (160 mg) induced increases of spectral power in fronto-temporal brain areas, Bacopa and the combination of Sideritis with high amounts of Bacopa extract produced attenuation of all waves except for delta in fronto-temporal brain areas. These differences were also documented by quantitative EEG maps in comparison to Placebo. A different action of both extracts was confirmed by discriminant analysis, where Sideritis extract and its combination with low Bacopa grouped together quite at distance to Bacopa and the combination of Sideritis with high Bacopa. A combination of Sideritis extract with a low amount of Bacopa should be tested with daily repetitive dosing for at least 4 weeks as a consequence.
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Pharmacological Classification of Herbal Extracts by Means of Comparison to Spectral EEG Signatures Induced by Synthetic Drugs in the Freely Moving Rat.
Article
Full-text available
  • Jul 2013
Herbal extracts targeting at the brain remain a continuous challenge to pharmacology. Usually, a number of different animal tests have to be performed in order to find a potential clinical use. Due to manifold possibly active ingredients biochemical approaches are difficult. A more holistic approach using a neurophysiological technique has been developed earlier in order to characterize synthetic drugs. Stereotactic implantation of four semi-microelectrodes into frontal cortex, hippocampus, striatum and reticular formation of rats allowed continuous wireless monitoring of field potentials (EEG) before and after drug intake. After frequency analysis (Fast Fourier Transformation) electric power was calculated for 6 ranges (delta, theta, alpha1, alpha2, beta1 and beta2). Data from 14 synthetic drugs - tested earlier and representative for different clinical indications - were taken for construction of discriminant functions showing the projection of the frequency patterns in a six-dimensional graph. Quantitative analysis of the EEG frequency pattern from the depth of the brain succeeded in discrimination of drug effects according to their known clinical indication (Dimpfel and Schober, 2003). Extracts from Valerian root, Ginkgo leav, Paullinia seed, Hop strobile, Rhodiola rosea root and Sideritis scardica herb were tested now under identical conditions. Classification of these extracts based on the matrix from synthetic drugs revealed that Valerian root and hop induced a pattern reminiscent of physiological sleep. Ginkgo and Paullinia appeared in close neighborhood of stimulatory drugs like caffeine or to an analgesic profile (tramadol). Rhodiola and Sideritis developed similar frequency patterns comparable to a psychostimulant drug (methylphenidate) as well to an antidepressive drug (paroxetine).
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Effect of an herbal extract of Sideritis scardica and B-vitamins on cognitive performance under stress: a pilot study
Article
  • May 2016
Chronic stress can impair cognitive functions including learning and memory. The current study investigated the reduction of (mental) stress and improvement of stress tolerance in 64 healthy men and women after six weeks intake of a dietary supplement containing an extract of Sideritis scardica and selected B-vitamins. Mental performance and visual attention were measured by Trail-Making Test (TMT) and Colour-Word-Test (CWT)before/after an acute stress stimulus (noise, CW-Interference). TMT improved upon product intake. The CWT reaction time accelerated upon product intake in situations of CW-Congruence (overall) (p=0.014), CW-conflict (overall) (p=0.024), CW-conflict (with noise) (p=0.001), CW-Congruence (without noise) (p=0.004) and CW-conflict (without noise) (p=0.017).CWT-changes upon product intake, differentiated for noise and CW-interference, showed (i) a bisection of CW-interference-related impairment of the reaction time in the presence of noise from 27 ms to 13.5 ms, (ii) a bisection of noise-related impairment of the reaction time in the presence of CW-conflict from 34 ms to 17 ms, (iii) an improvement of the impairment of the reaction time due to combined stress (noise plus CW-conflict) by 14.5 ms from 66 ms to 51.5 ms, (iv) despite of the improvement of the reaction time, no increase of the error rate. Safety blood parameters and the reporting of no adverse events argue for the product’s safety. These results may be relevant for persons solving cognitive tasks under conflict and/or noise (e.g. open-plan offices or car-driving) andsupport that the tested product alleviatesstress-induced impairment of executive functioning (working memory, cognitive flexibility, controlled behavioural inhibition).
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Neuroinflammation in Alzheimer's disease
Article
  • Apr 2015
Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Sideritis scardica Griseb., an endemic species of Balkan peninsula: Traditional uses, cultivation, chemical composition, biological activity
Article
  • Jan 2014
Ethnopharmacological relevance: Sideritis scardica Griseb. is an endemic species in the Balkan Peninsula. It is used in traditional medicine as a loosening agent in bronchitis and bronchial asthma; against the common cold and lung emphysema; in the treatment of inflammation, gastrointestinal disorders and coughs; and as an active constituent of dietary supplements for the prevention of anemia. This review aims to provide a comprehensive overview of the traditional use, phytochemistry, biological activity, cultivation, and extraction of Sideritis scardica and to highlight the gaps in our knowledge which deserves further research. Materials and methods: The present review is based on information collected from scientific journals, books, and electronic search. These sources include Scopus, Pubmed, Web of Science, and Google scholar as well as local books on ethnopharmacology and botany of this plant. Results: The reported data on phytochemical studies, biological activity, cultivation, extraction, and traditional uses have been reviewed. Variability in essential oil composition of wild growing and cultivated taxa depending on ecological conditions was discussed. Flavonoids, phenylethanoids, diterpenoids, aliphatic compounds, etc. identified so far have been summarized. A comparative study on the effectiveness of different methods, solvents, and parameters of extraction has also been discussed. A broad range of activities of plant extracts and fractions as antimicrobial, anti-inflammatory, cytotoxic, antioxidant, gastroprotective, antiglioma, and triple monoamine reuptake inhibition as well as cultivation of the species as an approach for conservation of the natural habitats and provision of herb with high and permanent quality has also been presented. Conclusions: Sideritis scardica has become very popular and widely advertised herb in Europe. Although some of ethnobotanical uses have been proved through in vitro experiments, further studies of the individual compounds or chemical class of compounds responsible for the pharmacological effects and the mechanisms of action are necessary. In addition, the toxicity and the side effects from the use of Sideritis scardica as well as clinical trails need attention. The variability in the chemical composition of this medicinal plant depending on the origin requires development of a protocol for its standardization. For the practice it is important to improve cultivation conditions in order to increase the accumulation of biologically active compounds and to obtain herb with permanent and good quality.
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Assay of urinary excretion of polyphenols after ingestion of a cup of mountain tea (Sideritis scardica) measured by HPLC-DAD-ESI-MS/MS
Article
Flavonoids and phenolic acids metabolite excreted in human urine after ingestion of Sideritis scardica decoction with characterized polyphenolic composition was studied. A feeding study was carried out with ten human volunteers and urine samples were collected for 24 h after ingestion of the Sidertis decoction. Polyphenol metabolites were identified and quantified in urine samples by HPLC with tandem mass spectrometric detection. 31 different metabolites of hypolaetin, methylhypolaetin, isoscutellarein, methylisoscutellarein and apigenin, and 32 phenolic acids metabolites were detected and quantified using a method validated for this purpose. The urinary excretion of polyphenol metabolites corresponded to 5% (n/n) of the intake of polyphenols from the Sideritis decoction. Flavonoid metabolites were dominant in urine samples with 87-94% of total polyphenolic metabolites content. The most abundant metabolites were methylhypolaetin and methylisoscutellarein glucuronides. Urinary excretion of isoscutellarein (35.61%) was ten times higher than that of hypolaetin (3.67%). Apigenin also showed high urinary excretion (32.46%).
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