Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B
There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/17/11/607 |
| _version_ | 1811187802185924608 |
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| author | Daniëlle Copmans Sara Kildgaard Silas A. Rasmussen Monika Ślęzak Nina Dirkx Michèle Partoens Camila V. Esguerra Alexander D. Crawford Thomas O. Larsen Peter A. M. de Witte |
| author_facet | Daniëlle Copmans Sara Kildgaard Silas A. Rasmussen Monika Ślęzak Nina Dirkx Michèle Partoens Camila V. Esguerra Alexander D. Crawford Thomas O. Larsen Peter A. M. de Witte |
| author_sort | Daniëlle Copmans |
| collection | DOAJ |
| description | There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus <i>Aspergillus insuetus</i>. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery. |
| first_indexed | 2024-04-11T14:08:40Z |
| format | Article |
| id | doaj.art-f55527d449b24d7bb5f42251a1982621 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T14:08:40Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-f55527d449b24d7bb5f42251a19826212022-12-22T04:19:48ZengMDPI AGMarine Drugs1660-33972019-10-01171160710.3390/md17110607md17110607Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120BDaniëlle Copmans0Sara Kildgaard1Silas A. Rasmussen2Monika Ślęzak3Nina Dirkx4Michèle Partoens5Camila V. Esguerra6Alexander D. Crawford7Thomas O. Larsen8Peter A. M. de Witte9Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumDepartment of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, DenmarkDepartment of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, DenmarkLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumDepartment of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, DenmarkLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumThere is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus <i>Aspergillus insuetus</i>. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery.https://www.mdpi.com/1660-3397/17/11/607pharmaseaepilepsyzebrafishmarine drug discoveryisoquinoline alkaloidstmc-120atmc-120btmc-120cpenicisochroman gustusorane b |
| spellingShingle | Daniëlle Copmans Sara Kildgaard Silas A. Rasmussen Monika Ślęzak Nina Dirkx Michèle Partoens Camila V. Esguerra Alexander D. Crawford Thomas O. Larsen Peter A. M. de Witte Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B Marine Drugs pharmasea epilepsy zebrafish marine drug discovery isoquinoline alkaloids tmc-120a tmc-120b tmc-120c penicisochroman g ustusorane b |
| title | Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B |
| title_full | Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B |
| title_fullStr | Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B |
| title_full_unstemmed | Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B |
| title_short | Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B |
| title_sort | zebrafish based discovery of antiseizure compounds from the north sea isoquinoline alkaloids tmc 120a and tmc 120b |
| topic | pharmasea epilepsy zebrafish marine drug discovery isoquinoline alkaloids tmc-120a tmc-120b tmc-120c penicisochroman g ustusorane b |
| url | https://www.mdpi.com/1660-3397/17/11/607 |
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