Synthetic Peucedanocoumarin IV Prevents alpha-Synuclein Neurotoxicity in an Animal Model of Parkinson's Disease
DC Field | Value | Language |
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dc.contributor.author | Kim, Heejeong | - |
dc.contributor.author | Maeng, Han-Joo | - |
dc.contributor.author | Kim, Ji Hun | - |
dc.contributor.author | Yoon, Jin-Ha | - |
dc.contributor.author | Oh, Yohan | - |
dc.contributor.author | Paek, Seung-Mann | - |
dc.contributor.author | Lee, Yunjong | - |
dc.date.accessioned | 2022-09-19T12:13:59Z | - |
dc.date.available | 2022-09-19T12:13:59Z | - |
dc.date.created | 2022-09-08 | - |
dc.date.issued | 2022-08 | - |
dc.identifier.issn | 1661-6596 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/171523 | - |
dc.description.abstract | Pathological protein inclusion formation and propagation are the main causes of neuronal dysfunction in diverse neurodegenerative diseases; therefore, current disease-modifying therapeutic strategies have targeted this disease protein aggregation process. Recently, we reported that peucedanocoumarin III (PCiii) is a promising therapeutic compound with the ability to disaggregate alpha-synuclein inclusion and protect dopaminergic neurons in Parkinson's disease (PD). Here, we found that trans-4 '-acetyl-3 '-tigloylkhellactone (racemic peucedanocoumarin IV [PCiv]), a structural isomer of PCiii with a higher synthetic yield presented a strong anti-aggregate activity to a degree comparable to that of PCiii. PCiv retained effective inhibitory function against beta-sheet aggregate-mimic beta 23 cytotoxicities and potently prevented alpha-synucleinopathy in alpha-synuclein preformed fibril (PFF)-treated mice cortical neurons. In detailed pharmacokinetic profiling of PCiv, oral administration of PCiv in rats exhibited an approximately 97-min half-life and 10% bioavailability. Moreover, tissue distribution analysis revealed favorable profiles of brain penetration with a 6.4 brain-to-plasma concentration ratio. The therapeutic efficacy of PCiv was further evaluated in a sporadic PD mouse model with a combinatorial co-injection of alpha-synuclein preformed fibril and recombinant adeno-associated virus expressing alpha-synuclein. Motor dysfunctions induced in this combinatorial alpha-synucleinopathy PD mouse model was almost completely rescued by PCiv diet administration, and this therapeutic effect is consistent with the marked prevention of dopaminergic neuron loss and suppression of alpha-synuclein aggregation. Taken together, our translational study suggests that PCiv is advantageous as a therapeutic agent for neurodegenerative diseases, especially with its good synthetic yield, high brain distribution, and anti-aggregate activity. PCiv may be useful in the management of alpha-synuclein inclusion formation and propagation at different stages of PD. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | MDPI | - |
dc.title | Synthetic Peucedanocoumarin IV Prevents alpha-Synuclein Neurotoxicity in an Animal Model of Parkinson's Disease | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Oh, Yohan | - |
dc.identifier.doi | 10.3390/ijms23158618 | - |
dc.identifier.scopusid | 2-s2.0-85136342932 | - |
dc.identifier.wosid | 000839178500001 | - |
dc.identifier.bibliographicCitation | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.23, no.15, pp.1 - 16 | - |
dc.relation.isPartOf | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | - |
dc.citation.title | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | - |
dc.citation.volume | 23 | - |
dc.citation.number | 15 | - |
dc.citation.startPage | 1 | - |
dc.citation.endPage | 16 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | Y | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalResearchArea | Chemistry | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Multidisciplinary | - |
dc.subject.keywordPlus | NEURODEGENERATION | - |
dc.subject.keywordPlus | PHOSPHORYLATION | - |
dc.subject.keywordAuthor | peucedanocoumarin IV | - |
dc.subject.keywordAuthor | organic synthesis | - |
dc.subject.keywordAuthor | Parkinson&apos | - |
dc.subject.keywordAuthor | s disease | - |
dc.subject.keywordAuthor | pharmacokinetics | - |
dc.subject.keywordAuthor | alpha-synuclein preformed fibril | - |
dc.subject.keywordAuthor | dopaminergic cell loss | - |
dc.identifier.url | https://www.mdpi.com/1422-0067/23/15/8618 | - |
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