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Molecules
2021 Aug 10;2616:. doi: 10.3390/molecules26164843.
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Neurorescue Effects of Frondoside A and Ginsenoside Rg3 in C. elegans Model of Parkinson''s Disease.
Chalorak P
,
Sanguanphun T
,
Limboonreung T
,
Meemon K
.
Abstract
Parkinson''s disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin can also be found in marine organisms such as the sea cucumber, but little is known about its effect in neurodegenerative disease, including PD. In this study, we investigated the anti-Parkinson effects of frondoside A (FA) from Cucumaria frondosa and ginsenoside Rg3 (Rg3) from Panax notoginseng in C. elegans PD model. Both saponins were tested for toxicity and optimal concentration by food clearance assay and used to treat 6-OHDA-induced BZ555 and transgenic α-synuclein NL5901 strains in C. elegans. Treatment with FA and Rg3 significantly attenuated DAergic neurodegeneration induced by 6-OHDA in BZ555 strain, improved basal slowing rate, and prolonged lifespan in the 6-OHDA-induced wild-type strain with downregulation of the apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2. Interestingly, only FA reduced α-synuclein aggregation, rescued lifespan in NL5901, and upregulated the protein degradation regulators, including ubh-4, hsf-1, hsp-16.1 and hsp-16.2. This study indicates that both FA and Rg3 possess beneficial effects in rescuing DAergic neurodegeneration in the 6-OHDA-induced C. elegans model through suppressing apoptosis mediators and stimulating antioxidant enzymes. In addition, FA could attenuate α-synuclein aggregation through the protein degradation process.
Figure 1. Structure of frondoside A (FA) and ginsenoside Rg3 (Rg3). (Drawn by Chemdraw).
Figure 2. Food clearance assay of C. elegans treated with 0–20 μM FA (A) and Rg3 (B). The asterisk (*) indicates a significant difference between the compound-treated worms compared with 1% DMSO-treated worms (p < 0.01). The experiment was performed independently at least three times (number of worms = 30 animals/group per replicate).
Figure 3. Effects of FA and Rg3 on restoration of 6-OHDA-induced DAergic neurodegeneration in C. elegans BZ555 strain. (A) GFP expression pattern in DAergic neurons of normal BZ555 strain, BZ555 exposed to 50 mM 6-OHDA, and BZ555 exposed to 50 mM 6-OHDA and treated with FA (0.1, 0.5, 1 μM) or Rg3 (1, 5, 10 μM). Scale bar, 50 μm. (B,C) Graphical representation for MFI of GFP expression in DAergic neurons treated with FA (B) and Rg3 (C) as measured by using ImageJ software. The hash (#) indicates a significant difference between 6-OHDA-induced and uninduced worms (p < 0.05). The asterisk (*) indicates a significant difference between the 6-OHDA-induced control worms and the FA/6-OHDA- or Rg3/6-OHDA-treated worms (p < 0.05). The experiment was performed independently at least three times (number of worms = 40–50 animals/group per replicate).
Figure 4. Graphical representations for the basal slowing rate in 6-OHDA-induced N2 C. elegans treated with FA (A) and Rg3 (B). The hash (#) indicates a significant difference between 6-OHDA-induced and uninduced worms (p < 0.05). The asterisk (*) indicates a significant difference between the 6-OHDA-induced control worms and the FA/6-OHDA- or Rg3/6-OHDA-treated worms (p < 0.05). The experiment was performed independently at least three times (number of worms = 40–50 animals/group per replicate).
Figure 5. Effects of FA and Rg3 on reduction of α-synuclein accumulation in C. elegans NL5901 strain. (A) YFP expression of the α-synuclein accumulation in muscles of normal NL5901, NL5901 treated with various doses of FA or Rg3. Scale bar, 50 μm. (B,C) Graphical representations for MFI of YFP expression of α-synuclein accumulation treated with FA (B) and Rg3 (C) as measured by using ImageJ software. The asterisk (*) indicates a significant difference between the control DMSO-treated worms and the FA- or Rg3-treated worms (p < 0.05). The experiment was performed independently at least three times (number of worms = 40–50 animals/group per replicate).
Figure 6. Effects of FA and Rg3 on lifespan of 6-OHDA-induced and transgenic α-synuclein NL5901 worms. (A) Survival curves of wild-type N2, 6-OHDA-induced, and FA/Rg3-treated worms. (B) Survival curves of wild-type N2, DMSO-cultured NL5901 and FA/Rg3-treated NL5901. The experiment was performed independently at least three times (number of worms = 30–40 animals/group per replicate).
Figure 7. (A) Fold change of gene expression levels (2−(ΔΔCq)) of apoptosis genes in N2 worms treated with 6-OHDA, 6-OHDA/FA and 6-OHDA/Rg3. (B) Fold change of gene expression levels of protein degradation regulator genes in NL5901 worms treated with FA and Rg3. All targeted genes were measured in triplicate, and three independent biological triplicates were performed in each condition. The hash (#) indicates a significant difference between 6-OHDA-induced and uninduced worms (p < 0.05). The asterisk (*) indicates a significant difference between the control worms and the FA or Rg3-treated worms (p < 0.05).
