Pawanrat Chalorak1, Nilubon Sornkaew2, Preeyanuch Manohong3, Nakorn Niamnont4, Nawaphat Malaiwong5, Tanapol Limboonreung6, Prasert Sobhon7, Michael Aschner8, Krai Meemon9. 1. Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand. Electronic address: airpawanratch@gmail.com. 2. Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi, Bang Mod, Bangkok, 10140, Thailand. Electronic address: NILUBON_JIB@hotmail.com. 3. Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi, Bang Mod, Bangkok, 10140, Thailand. Electronic address: preeyanuch_m01@hotmail.co.th. 4. Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi, Bang Mod, Bangkok, 10140, Thailand. Electronic address: nakorn.nia@kmutt.ac.th. 5. Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand. Electronic address: n-malaiwong@hotmail.com. 6. Division of Oral Biology, Faculty of Dentistry, King Mongkut's Institute of Technology Ladkrabang, Ladkrabang, Bangkok, 10520, Thailand. Electronic address: Tanapol.li@kmitl.ac.th. 7. Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand. Electronic address: prasertsobhon@gmail.com. 8. Department of Molecular Pharmacology, Neuroscience, and Pediatrics, Albert Einstein College of Medicine, Morris Park Avenue, Bronx, NY, 10461, USA. Electronic address: michael.aschner@einsteinmed.org. 9. Department of Anatomy, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand. Electronic address: krai.mee@mahidol.ac.th.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Holothuria (Metriatyla) scabra Jaeger (H. scabra), sea cucumber, is the marine organism that has been used as traditional food and medicine to gain the health benefits since ancient time. Although our recent studies have shown that crude extracts from H. scabra exhibited neuroprotective effects against Parkinson's disease (PD), the underlying mechanisms and bioactive compounds are still unknown. AIM OF THE STUDY: In the present study, we examined the efficacy of purified compounds from H. scabra and their underlying mechanism on α-synuclein degradation and neuroprotection against α-synuclein-mediated neurodegeneration in a transgenic Caenorhabditis elegans PD model. MATERIAL AND METHODS: The H. scabra compounds (HSEA-P1 and P2) were purified and examined for their toxicity and optimal dose-range by food-clearance and lifespan assays. The α-synuclein degradation and neuroprotection against α-synuclein-mediated neurodegeneration were determined using transgenic C. elegans model, Punc-54::α-syn and Pdat-1:: α-syn; Pdat-1::GFP, respectively, and then further investigated by determining the behavioral assays including locomotion rate, basal slowing rate, ethanol avoidance, and area-restricted searching. The underlying mechanisms related to autophagy were clarified by quantitative PCR and RNAi experiments. RESULTS: Our results showed that HSEA-P1 and HSEA-P2 significantly diminished α-synuclein accumulation, improved motility deficits, and recovered the shortened lifespan. Moreover, HSEA-P1 and HSEA-P2 significantly protected dopaminergic neurons from α-synuclein toxicity and alleviated dopamine-associated behavioral deficits, i.e., basal slowing, ethanol avoidance, and area-restricted searching. HSEA-P1 and HSEA-P2 also up-regulated autophagy-related genes, including beclin-1/bec-1, lc-3/lgg-1, and atg-7/atg-7. RNA interference (RNAi) of these genes in transgenic α-synuclein worms confirmed that lc-3/lgg-1 and atg-7/atg-7 were required for α-synuclein degradation and DAergic neuroprotection activities of HSEA-P1 and HSEA-P2. NMR and mass spectrometry analysis revealed that the HSEA-P1 and HSEA-P2 contained diterpene glycosides. CONCLUSION: These findings indicate that diterpene glycosides extracted from H. scabra decreases α-synuclein accumulation and protects α-synuclein-mediated DAergic neuronal loss and its toxicities via lgg-1 and atg-7.
ETHNOPHARMACOLOGICAL RELEVANCE: Holothuria (Metriatyla) scabra Jaeger (H. scabra), sea cucumber, is the marine organism that has been used as traditional food and medicine to gain the health benefits since ancient time. Although our recent studies have shown that crude extracts from H. scabra exhibited neuroprotective effects against Parkinson's disease (PD), the underlying mechanisms and bioactive compounds are still unknown. AIM OF THE STUDY: In the present study, we examined the efficacy of purified compounds from H. scabra and their underlying mechanism on α-synuclein degradation and neuroprotection against α-synuclein-mediated neurodegeneration in a transgenic Caenorhabditis elegans PD model. MATERIAL AND METHODS: The H. scabra compounds (HSEA-P1 and P2) were purified and examined for their toxicity and optimal dose-range by food-clearance and lifespan assays. The α-synuclein degradation and neuroprotection against α-synuclein-mediated neurodegeneration were determined using transgenic C. elegans model, Punc-54::α-syn and Pdat-1:: α-syn; Pdat-1::GFP, respectively, and then further investigated by determining the behavioral assays including locomotion rate, basal slowing rate, ethanol avoidance, and area-restricted searching. The underlying mechanisms related to autophagy were clarified by quantitative PCR and RNAi experiments. RESULTS: Our results showed that HSEA-P1 and HSEA-P2 significantly diminished α-synuclein accumulation, improved motility deficits, and recovered the shortened lifespan. Moreover, HSEA-P1 and HSEA-P2 significantly protected dopaminergic neurons from α-synuclein toxicity and alleviated dopamine-associated behavioral deficits, i.e., basal slowing, ethanol avoidance, and area-restricted searching. HSEA-P1 and HSEA-P2 also up-regulated autophagy-related genes, including beclin-1/bec-1, lc-3/lgg-1, and atg-7/atg-7. RNA interference (RNAi) of these genes in transgenic α-synuclein worms confirmed that lc-3/lgg-1 and atg-7/atg-7 were required for α-synuclein degradation and DAergic neuroprotection activities of HSEA-P1 and HSEA-P2. NMR and mass spectrometry analysis revealed that the HSEA-P1 and HSEA-P2 contained diterpene glycosides. CONCLUSION: These findings indicate that diterpene glycosides extracted from H. scabra decreases α-synuclein accumulation and protects α-synuclein-mediated DAergic neuronal loss and its toxicities via lgg-1 and atg-7.
Authors: Adam J Harrington; Talene A Yacoubian; Sunny R Slone; Kim A Caldwell; Guy A Caldwell Journal: J Neurosci Date: 2012-02-08 Impact factor: 6.167
Authors: Rakesh Bodhicharla; Archana Nagarajan; Jody Winter; Ademola Adenle; Aamir Nazir; Declan Brady; Kelly Vere; Jo Richens; Paul O'Shea; David R Bell; David de Pomerai Journal: CNS Neurol Disord Drug Targets Date: 2012-12 Impact factor: 4.388