TY  - GEN
A1  - Link, Pille
N2  - 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 (A?) 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 A? peptide in
muscles, several extracts that could reduce A? 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 A? aggregates by 30 %, this extract could also counteract A? 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 A? aggregation by 26 % and counteracting A? toxicity
in paralysis assay (1.2 h delay in PT50). It also affected serotonergic neurotransmission
in C. elegans with neuronal A? 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 A? 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 A?
toxicity and its antioxidant activity in vivo. The dichloromethane extract of this plant delayed
the A?-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 A? 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.
Y1  - 2018///
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/20359/
ID  - heidok20359
AV  - public
TI  - Natural products against neurodegenerative diseases: effects in the model organism Caenorhabditis elegans
ER  -