Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease
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...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| author | Heejeong Kim Han-Joo Maeng Ji Hun Kim Jin-Ha Yoon Yohan Oh Seung-Mann Paek Yunjong Lee |
| author_facet | Heejeong Kim Han-Joo Maeng Ji Hun Kim Jin-Ha Yoon Yohan Oh Seung-Mann Paek Yunjong Lee |
| author_sort | Heejeong Kim |
| collection | DOAJ |
| description | 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 α-synuclein inclusion and protect dopaminergic neurons in Parkinson’s disease (PD). Here, we found that <i>trans</i>-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 β-sheet aggregate-mimic β23 cytotoxicities and potently prevented α-synucleinopathy in α-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 α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-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 α-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 α-synuclein inclusion formation and propagation at different stages of PD. |
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| language | English |
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| spelling | doaj.art-c6de75b53a784716861a368f03f0f4272023-12-01T22:58:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012315861810.3390/ijms23158618Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s DiseaseHeejeong Kim0Han-Joo Maeng1Ji Hun Kim2Jin-Ha Yoon3Yohan Oh4Seung-Mann Paek5Yunjong Lee6Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, KoreaCollege of Pharmacy, Gachon University, Incheon 21936, KoreaDepartment of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, KoreaCollege of Pharmacy, Gachon University, Incheon 21936, KoreaDepartment of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju Daero 501, Jinju 52828, KoreaDepartment of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, KoreaPathological 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 α-synuclein inclusion and protect dopaminergic neurons in Parkinson’s disease (PD). Here, we found that <i>trans</i>-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 β-sheet aggregate-mimic β23 cytotoxicities and potently prevented α-synucleinopathy in α-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 α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-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 α-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 α-synuclein inclusion formation and propagation at different stages of PD.https://www.mdpi.com/1422-0067/23/15/8618peucedanocoumarin IVorganic synthesisParkinson’s diseasepharmacokineticsα-synuclein preformed fibrildopaminergic cell loss |
| spellingShingle | Heejeong Kim Han-Joo Maeng Ji Hun Kim Jin-Ha Yoon Yohan Oh Seung-Mann Paek Yunjong Lee Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease International Journal of Molecular Sciences peucedanocoumarin IV organic synthesis Parkinson’s disease pharmacokinetics α-synuclein preformed fibril dopaminergic cell loss |
| title | Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease |
| title_full | Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease |
| title_fullStr | Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease |
| title_full_unstemmed | Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease |
| title_short | Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson’s Disease |
| title_sort | synthetic peucedanocoumarin iv prevents α synuclein neurotoxicity in an animal model of parkinson s disease |
| topic | peucedanocoumarin IV organic synthesis Parkinson’s disease pharmacokinetics α-synuclein preformed fibril dopaminergic cell loss |
| url | https://www.mdpi.com/1422-0067/23/15/8618 |
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