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Neuroprotektive Wirkung von Sideritis scardica Griseb. in Caenorhabditis elegans als Modellorganismus für neurodegenerative Erkrankungen
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Sideritis scardica Griseb., also known as Greek mountain tea, is a plant that belongs to the family of Lamiaceae. It is endemic to the Balkan region, where the herb is traditionally used against a broad range of afflictions, mostly as an infusion. Over the past few years, S. scardica has been scientifically investigated for the pharmacological properties it is said to have, especially focusing on the effects in the central nervous system, such as an improved cognitive performance and the reduction of β-amyloid plaques which are typical in Alzheimer's disease. Following this issue, the main goal of the present study was to examine whether extracts of Greek mountain tea counteract further pathomechanisms of this and other neurodegenerative disorders which are a rising health concern in our ageing society.
For this purpose six hydroalcoholic S. scardica extracts of different lipophilicity, that were produced and phytochemically analysed by Finzelberg GmbH & Co. KG, were investigated for their neuroprotective activity in the model organism Caenorhabditis elegans. Additionally, six fractions of one of the most potent extracts, seven isolated pure compounds and extracts of some well-known medicinal plants were tested.
The mid-polar extracts of S. scardica in particular, as well as the more lipophilic fractions and the phenylethanoid glycosides, were counteracting the aggregation or toxicity of β-amyloid peptides, α-synuclein, 6-hydroxydopamine, tau- and polyglutamine proteins in vivo, whereas they did not reveal any antioxidant properties in the nematodes. The spectrum of activities of S. scardica was especially comparable with that of Bacopa monnieri (Brahmi), a plant used in ayurvedic medicine.
The alleviation of the neurotoxicity of the proteins and compounds make S. scardica extracts interesting for the preventive or therapeutic treatment of Alzheimer's, Parkinson's, Huntington's and other neurodegenerative diseases. The phenylethanoids could be identified as active constituents, although synergistic effects between extractives of different polarity remain probable and have to be taken into consideration. Also, a hypothetical mode of action could be postulated: the bonding of polyphenols to the peptides, directly inhibiting their aggregation to toxic oligomers or plaques and fibrils.
In the present study, the activity of hydroalcoholic Sideritis scardica extracts against hallmarks of Alzheimer's disease could be affirmed and for the first time, positive effects on further neurotoxic substances could be shown, expanding the neuropharmacological profile of the Greek mountain tea. As some studies on vertebrates and humans assessing the influence on cognitive performance and proving the harmlessness have already been conducted, high-quality clinical studies investigating the preventive or therapeutic efficacy against Alzheimer's etc. should be performed.
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Дисертационният труд представлява обемно и подробно проведено изследване, което включва, освен оценка на влиянието на основните екстракционни параметри върху добива на фенолни съединения от диворастящите, нетрадиционни за България, растителни видове - Cistus incanus L. (памуклийка), Trachystemon orientalis L. (източен лопох) и Phyllirea latifolia L. (грипа) от Странджа планина, така и качествено и количествено определяне на някои антиоксиданти в техни екстракти с разработен и валидиран за целта течнохроматографски метод за анализ. В допълнение за първи път е моделирана и кинетиката на ултразвукова екстракция на листа и на стъбла от Cistus incanus спрямо най-значимите параметри на екстракция. Освен от работните условия по време на екстракция, количеството на полезните компоненти в екстрактите от Cistus incanus се влияе от вида екстрахирана надземна част, географския произход, сезонната изменчивост и начина на съхранение на суровината. Като цяло системното и задълбочено изследване на екстракцията на фенолни компоненти от Cistus incanus, Trachystemon orientalis и Phyllirea latifolia, както и установените високи количества на антиоксиданти в техните екстракти, демонстрират възможностите на приложение на непроучените досега български находища на диворастящите видове в областта на храните, козметиката и лекарствата.
Present study investigates the effect of storage (at room temperature and at a frozen state) of Cistus incanus leaves and its hard-coated seeds on the total polyphenol content and the antioxidant capacity in view of the extraction carried out in 50 % ethanol-in water solution. A correlation between the polyphenol content and the antioxidant activity of the leaves stored at room temperature is elucidated. The frozen stored material generates better extraction efficiency and keeps a very high antioxidant activity. This investigation demonstrates that Cistus incanus from Strandja Mountain, Bulgaria is an important source of polyphenols and antioxidant activity. The latter is present in leaves stored for a couple of years. The results from this study contribute to better understanding the extraction process of this non-traditional Bulgarian herb.
Aggregated forms of α-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson's disease (PD). However, the molecular mechanisms underlying the pathogenic effects of α-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human α-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human α-synuclein at N103 in an age-dependent manner. AEP is highly activated in human brains with PD, and it fragments α-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved α-synuclein1-103 fragment in the substantia nigra induces both dopaminergic neuronal loss and movement defects in mice. In contrast, inhibition of AEP-mediated cleavage of α-synuclein (wild type and A53T mutant) diminishes α-synuclein's pathologic effects. Together, these findings support AEP's role as a key mediator of α-synuclein-related etiopathological effects in PD.
Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.
α-Synuclein is a major constituent of pathological intracellular inclusion bodies, a common feature of several neu- rodegenerative diseases. Two missense mutations in the α-synuclein gene have been identified in confirmed autosomal-dominant familial Parkinson's disease, which segregate with the illness. However, the physiological function of α-synuclein remains unknown. After biochemical investigations we have revealed tubulin to be an α-synuclein associated/binding protein. Here, we show that α-synuclein induces polymerization of purified tubulin into microtubules. Mutant forms of α-synuclein lose this potential. The binding site of α-synuclein to tubulin is identified, and co-localization of α-synuclein with microtubules is shown in cultured cells. To our knowledge, this is the first demonstration of microtubule-polymerizing activity of α-synuclein. Now we can see a striking resemblance between α-synuclein and tau: both have the same physiological function and pathological features, making abnormal structures in diseased brains known as synucleinopathies and tauopathies. The discovery of a physiological role for α-synuclein may provide a new dimension in researches into the mechanisms of α-synuclein-associated neurodegenerative diseases.
Expansion of polyglutamine stretches in several proteins cause neurodegenerative amyloidoses, including Huntington disease. In yeast, mutant huntingtin (mHtt) with a stretch of 103 glutamine residues (HttQ103) forms toxic aggregates. A range of yeast strains have been used to elucidate the mechanisms of mHtt toxicity, and have revealed perturbations of various unrelated processes. HttQ103 aggregates can induce aggregation of cellular proteins, many of which contain glutamine/asparagine-rich regions, including Sup35 and Def1. In the strain 74-D694 HttQ103, toxicity is related to aggregation-mediated depletion of soluble Sup35 and its interacting partner Sup45. Def1 was also implicated in mHtt toxicity, since its lack detoxified HttQ103 in another yeast strain, BY4741. Here we show that in BY4742, deletion of DEF1 lowers HttQ103 toxicity and decreases the amount of its polymers, but does not affect co-polymerization of Sup35. Furthermore, in contrast to 74-D694, increasing the levels of soluble Sup35 and Sup45 does not alleviate toxicity of HttQ103 in BY4742. These data demonstrate a difference in the mechanisms underlying mHtt toxicity in different yeast strains and suggest that in humans with Huntington disease, neurons of different brain compartments and cells in other tissues can also be damaged by different mechanisms.
Depression is a heterogeneous mood disorder that has been classified and treated in a variety of ways. Although a number of synthetic drugs are being used as standard treatment for clinically depressed patients, they have adverse effects that can compromise the therapeutic treatment. Thus, it is worthwhile to look for antidepressants from plants with proven advantage and favourable benefit-to-risk ratio. A number of medicinal plants per se and medicines derived from these plants have shown antidepressant properties by virtue of their medicinal constituents. The causes of depression are decreased brain levels of monoamines like noradrenaline, dopamine and serotonin. Therefore, drugs restoring the reduced levels of these monoamines in the brain either by inhibiting monoamine oxidase or by inhibiting reuptake of these neurotransmitters might be fruitful in the treatment of depression. The present review is focused on the medicinal plants and plant-based formulations having antidepressant activity in animal studies and in humans. © 2018, National Institute of Science Communication and Information Resources (NISCAIR). All rights reserved.
Increasing the acetylcholine level and fighting the neuroinflammation has always been taken as a treatment strategy for Alzheimer's disease (AD). Forsythoside A is a major component in Forsythia suspensa (Thunb.) Vahl (F. suspensa, Lianqiao in Chinese) that has been traditionally used as Chinese herbal medicine to treat the inflammation in China. This study examined the inhibitory acetylcholinesterase activities of Forsythoside A at chemical and biological level. Forsythoside A inhibited acetylcholinesterase in a mixed type of inhibition, with Ki of 47.68 μM. Docking analysis strongly supported these findings. In PC12 cells Forsythoside A increased cell viability and suppressed acetylcholinesterase increased by Aβ25-35, thus alleviated the corresponding apoptosis. Taken together, these results suggest that Forsythoside A has the protective effects on Aβ25-35-induced apoptosis in PC12 cells by downregulating acetylcholinesterase, making it a potential functional food ingredient or drug candidate for the treatment of AD.
Echinacoside is a phenylethanoid glycoside and possesses neuroprotective activity in vitro and in vivo. This study investigates the role of amyloid cascade and central neuronal function on the protective effects of echinacoside in amyloid β peptide 1-42 (Aβ 1-42)-treated SH-SY5Y cells and Aβ 1-42-infused rat. Echinacoside inhibited Aβ 1-42 oligomerization in vitro and restored the cell viability that was reduced by Aβ 1-42 in SH-SY5Y cells. Intracisternal infusion with Aβ 1-42 by osmotic pump caused cognitive deficits, the increase in amyloid deposition and acetylcholinesterase activities, and the decrease in the levels of brain’s acetylcholine and dopamine. Echinacoside reduced cognitive deficits and amyloid deposition, and reversed cortical cholinergic dysfunction that were caused by Aβ 1-42 in rats. Echinacoside further reversed the memory impairment on Morris water maze caused by scopolamine in mice. Therefore, we suggest that echinacoside ameliorated cognitive dysfunction that was caused by Aβ 1-42 by blocking amyloid deposition via inhibiting amyloid oligomerization and reversing cortical cholinergic neuronal function via decreasing amyloid neurotoxicity.