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Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease
The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to dis...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862101/ https://www.ncbi.nlm.nih.gov/pubmed/31689937 http://dx.doi.org/10.3390/ijms20215481 |
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author | Ham, Sangwoo Kim, Heejeong Yoon, Jin-Ha Kim, Hyojung Song, Bo Reum Choi, Jeong-Yun Lee, Yun-Song Paek, Seung-Mann Maeng, Han-Joo Lee, Yunjong |
author_facet | Ham, Sangwoo Kim, Heejeong Yoon, Jin-Ha Kim, Hyojung Song, Bo Reum Choi, Jeong-Yun Lee, Yun-Song Paek, Seung-Mann Maeng, Han-Joo Lee, Yunjong |
author_sort | Ham, Sangwoo |
collection | PubMed |
description | The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation. |
format | Online Article Text |
id | pubmed-6862101 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68621012019-12-05 Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease Ham, Sangwoo Kim, Heejeong Yoon, Jin-Ha Kim, Hyojung Song, Bo Reum Choi, Jeong-Yun Lee, Yun-Song Paek, Seung-Mann Maeng, Han-Joo Lee, Yunjong Int J Mol Sci Article The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation. MDPI 2019-11-04 /pmc/articles/PMC6862101/ /pubmed/31689937 http://dx.doi.org/10.3390/ijms20215481 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ham, Sangwoo Kim, Heejeong Yoon, Jin-Ha Kim, Hyojung Song, Bo Reum Choi, Jeong-Yun Lee, Yun-Song Paek, Seung-Mann Maeng, Han-Joo Lee, Yunjong Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease |
title | Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease |
title_full | Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease |
title_fullStr | Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease |
title_full_unstemmed | Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease |
title_short | Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease |
title_sort | therapeutic evaluation of synthetic peucedanocoumarin iii in an animal model of parkinson’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862101/ https://www.ncbi.nlm.nih.gov/pubmed/31689937 http://dx.doi.org/10.3390/ijms20215481 |
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