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Natural products against neurodegenerative diseases: effects in the model organism Caenorhabditis elegans

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Abstract

Neurodegenerative diseases are a growing burden in the modern ageing societies. Especially Alzheimer’s disease (AD)—the most common form of dementia—has gained lot of attention lately. Although several drugs are available to enhance the life-quality of people with AD, none of them can stop the progression or cure this disease. Therefore new medications for treatment and prevention are needed. Medicinal plants are a rich source for drug leads and active compounds. Furthermore, plant extracts are potential multitarget drugs that can be particularly useful for diseases with complex pathology like AD. Therefore, in the present work plants from Traditional Chinese Medicine (TCM) were tested for their efficacy against two prominent pathological markers in AD: beta-amyloid (Aβ) aggregates and oxidative damage. For the present study the model organism Caenorhabditis elegans was deployed. In a screening of 55 TCM plant extracts on a C. elegans strain expressing human Aβ peptide in muscles, several extracts that could reduce Aβ aggregation were identified. From those the three most active ones were chosen for further evaluation. The methanol extract of Glycyrrhiza uralensis proved to have the best characteristics for therapeutic use. Additionally to the reduction of Aβ aggregates by 30 %, this extract could also counteract Aβ toxicity in a paralysis assay by increasing the mean time of paralysis (PT50) by 1.8 h and showed antioxidant activity in the heat shock protein (HSP) expression assay. The major compounds in the G. uralensis extract were identified via LC-MS/MS. Four substances—glycyrrhizic acid (GA), glycyrrhetinic acid (GRA), liquiritigenin (LG), and isoliquiritigenin (ILG)—were chosen as possible active compounds. From those ILG showed the strongest activity by reducing Aβ aggregation by 26 % and counteracting Aβ toxicity in paralysis assay (1.2 h delay in PT50). It also affected serotonergic neurotransmission in C. elegans with neuronal Aβ expression. Furthermore, significant antioxidant activity was shown in the HSP expression assay, and the survival of worms under oxidative stress was increased by 82 % after treatment with ILG. This compound could induce nuclear translocation of the transcription factor DAF-16 that is responsible for stress resistance and longevity in C. elegans. The mechanism of action of ILG in counteracting Aβ toxicity could therefore involve hormesis and modulation of serotonergic neurotransmission. The present work also reports for the first time the effect of Carlina acaulis against Aβ toxicity and its antioxidant activity in vivo. The dichloromethane extract of this plant delayed the Aβ-induced paralysis by 1.6 h. GLC-MS analysis identified Carlina oxide as the main compound in this extract. Carlina oxide alone was not as active as the extract in paralysis assay, but it was responsible for the antioxidant activity. Both the extract and Carlina oxide were active in the HSP expression assay and could induce DAF-16 delocalisation. The mechanism of action for C. acaulis against Aβ toxicity still needs further study, although hormetic effects and the antioxidant activity may contribute to this effect. The plants and compounds identified in this study should be considered for further investigation in vertebrate models. Especially their bioavailability and drug safety need broader attention. The initial results reported here suggest G. uralensis, C. acaulis, and ILG as possible candidates for prevention or treatment of AD. Their positive effects counteracting protein aggregation and oxidative stress might also be useful against other neurodegenerative diseases and for healthy ageing in general.

Item Type: Dissertation
Supervisor: Wink, Prof. Dr. Michael
Date of thesis defense: 24 February 2016
Date Deposited: 09 Mar 2016 09:35
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Subjects: 500 Natural sciences and mathematics
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