Neurorestorative properties of 2-butoxytetrahydrofuran from Holothuria scabra via activation of stress resistance and detoxification in a 6-OHDA-induced C. elegans model of Parkinson's disease

Abstract

Holothuria scabra (H. scabra), a marine organism traditionally known for its health benefits, has been utilized in both food and medicine. Our previous studies indicated that 2-butoxytetrahydrofuran (2-BTHF), which is isolated from H. scabra, possesses the potential to alleviate amyloid-β and α-synuclein accumulations associated with Alzheimer's and Parkinson's diseases (AD and PD), respectively. However, the mechanisms through which 2-BTHF mitigates PD-related neurotoxicity remain unclear. In this study, we investigated the effects of 2-BTHF on a 6-hydroxydopamine (6-OHDA)-induced Caenorhabditis elegans (C. elegans) model. Our results demonstrated that 2-BTHF recovered dopaminergic (DAergic) neurons from degeneration and restored dopamine-related behaviors. Furthermore, 2-BTHF reduced reactive oxygen species (ROS) production, preserved mitochondrial fluorescence, and decreased both mitochondrial and cytoplasmic unfolded protein responses (UPRmt and UPRcyto) activation. Transcriptome sequencing analysis revealed the critical roles of various systems, including the immune system, nervous system, glutathione (GSH) metabolism, xenobiotics, terpenoids, energy metabolism, cell growth and death, and aging-related longevity pathways. Additionally, 2-BTHF showed potential interactions with stress resistance and detoxification transcription factors, promoting the nuclear translocation of DAF-16 and SKN-1, which in turn activated their targets, including SOD-3, CTL-2, GCS-1, and GST-4. Moreover, 2-BTHF increased total GSH levels and reduced the ced-3-related cascade. This study demonstrates that 2-BTHF holds promise as a therapeutic agent for treating 6-OHDA-induced DAergic neurodegeneration in the C. elegans model.