Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction.

Taweesak Tangrodchanapong,Nilubon Sornkaew,Laphatrada Yurasakpong,Nakorn Niamnont,Chanin Nantasenamat,Prasert Sobhon,Krai Meemon

doi:10.3390/molecules26082195

Taweesak Tangrodchanapong, Nilubon Sornkaew + Show 5 more

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https://doi.org/10.3390/molecules26082195

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Abstract

The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer’s disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aβ aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aβ toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aβ monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF’s potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aβ aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aβ toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorders and was reported in a recent study as the third largest contributor to global, neurological, disabilityadjusted life-years [1]
This study suggested that heat shock factor 1 (HSF-1) may be a potential target of the 2-BTHF (5) molecule. These findings indicated that the protective effect of 2-BTHF (5) against Aβ aggregate toxicity resulting in paralysis may be mediated by its activations of the autophagic pathway and HSF-1’s transcriptional activities
Since reactive oxygen species (ROS) production from Aβ pro-fibril aggregates has been reported to be a known cause of paralysis in CL4176 worms [37], we evaluated whether the reduction of ROS level by 2-BTHF (5) would concurrently occur with the reduction of Aβ oligomers, the main toxic species

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorders and was reported in a recent study as the third largest contributor to global, neurological, disabilityadjusted life-years [1]. Analytical research indicated that among neurodegenerative diseases related to protein aggregation, AD showed the highest relevance to be curable by natural products (up to 79%) [2] This is one of the reasons that metabolites from natural organisms—either plants or animals—may contain the derivatives needed to develop therapeutic agents against AD. The extracts could exert a significant effect on reducing α-synuclein aggregation in the C. elegans model of Parkinson’s disease (PD) [8] Regarding this therapeutic potential against the aggregation of α-synuclein, as categorized in a group of proteinopathy-causing diseases including AD by Aβ [9,10], we hypothesized that purified compounds isolated from the H. scabra sea cucumber may have similar mitigatory effect against Aβ aggregates via IIS’s transcription factor

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