ABSTRACT
Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-ß aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 µM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.
Subject(s)
Animals, Genetically Modified , Caenorhabditis elegans , Disease Models, Animal , Furans , Holothuria , Oxidative Stress , alpha-Synuclein , Animals , Caenorhabditis elegans/drug effects , alpha-Synuclein/metabolism , Oxidative Stress/drug effects , Furans/pharmacology , Parkinson Disease/metabolism , Parkinson Disease/drug therapy , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Molecular Docking Simulation , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , HumansABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disease which is still incurable. Sea cucumber-derived compounds have been reported to be promising candidate drugs for treating age-related neurological disorders. The present study evaluated the beneficial effects of the Holothuria leucospilota (H. leucospilota)-derived compound 3 isolated from ethyl acetate fraction (HLEA-P3) using Caenorhabditis elegans PD models. HLEA-P3 (1 to 50 µg/mL) restored the viability of dopaminergic neurons. Surprisingly, 5 and 25 µg/mL HLEA-P3 improved dopamine-dependent behaviors, reduced oxidative stress and prolonged lifespan of PD worms induced by neurotoxin 6-hydroxydopamine (6-OHDA). Additionally, HLEA-P3 (5 to 50 µg/mL) decreased α-synuclein aggregation. Particularly, 5 and 25 µg/mL HLEA-P3 improved locomotion, reduced lipid accumulation and extended lifespan of transgenic C. elegans strain NL5901. Gene expression analysis revealed that treatment with 5 and 25 µg/mL HLEA-P3 could upregulate the genes encoding antioxidant enzymes (gst-4, gst-10 and gcs-1) and autophagic mediators (bec-1 and atg-7) and downregulate the fatty acid desaturase gene (fat-5). These findings explained the molecular mechanism of HLEA-P3-mediated protection against PD-like pathologies. The chemical characterization elucidated that HLEA-P3 is palmitic acid. Taken together, these findings revealed the anti-Parkinson effects of H. leucospilota-derived palmitic acid in 6-OHDA induced- and α-synuclein-based models of PD which might be useful in nutritional therapy for treating PD.
Subject(s)
Holothuria , Neurodegenerative Diseases , Parkinson Disease , Animals , Parkinson Disease/metabolism , Caenorhabditis elegans/metabolism , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , alpha-Synuclein/pharmacology , Holothuria/metabolism , Palmitic Acid/pharmacology , Neurodegenerative Diseases/drug therapy , Oxidopamine , Animals, Genetically Modified , Dopaminergic Neurons , Disease Models, AnimalABSTRACT
The anti-apoptosis effect of germinated brown rice (GBR) focusing on differentiated HT22 cells results in improved nutritional values after the germination process of GBR which contains total phenolic compounds and γ-aminobutyric acid (GABA). Cell death induced by 5 mM glutamate was investigated for 24 h to determine whether GBR mediates cell death through GABA receptors by using antagonists. The results showed that GBR (100 µg/ml) suppressed glutamate-induced cytotoxicity and caused arrest at the G1/S phase of the cell cycle in differentiated HT22 cells. Furthermore, GBR significantly decreased the expression level of c-Jun, while its active form, p-c-Jun, is the downstream product of the JNK-mediated apoptotic pathway and causes subsequent cell death. In addition, bicuculline (12.5 nM), a GABAA antagonist, could eliminate GBR effects, but phaclofen (1 mM), a GABAB antagonist, could not. Surprisingly, GBR exhibited a better neuroprotective effect than a pure commercial GABA compound (0.115 µM). These results indicated that GBR possessed high anti-apoptotic activity and inhibited cell death in differentiated HT22 cells by perturbing re-entry of the cell cycle and apoptosis via the GABAA receptor. Hence, GBR could be further used as a valuable nutritional compound to prevent apoptosis-induced neurodegenerative diseases.
