Identification of GSK-3 as a Potential Therapeutic Entry Point for Epilepsy
| Autor: | RuAngelie Edrada-Ebel, Joëlle N Chabwine, Pascal Byenda Balegamire, Camila V. Esguerra, Najat Aourz, Appolinary Kamuhabwa, Ann-Sophie K. Serruys, Ilse Julia Smolders, Fred Van Leuven, Tatiana Afrikanova, Alexander D. Crawford, Alexander I Grey, Laura Walrave, Peter de Witte |
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| Přispěvatelé: | Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology, Faculty of Medicine and Pharmacy, Alliance for Modulation in Epilepsy |
| Rok vydání: | 2018 |
| Předmět: |
Male
Indoles medicine.medical_treatment Cognitive Neuroscience Pharmacology Inhibitory postsynaptic potential Biochemistry 6 Hz indirubin RS 03 medical and health sciences chemistry.chemical_compound Epilepsy Glycogen Synthase Kinase 3 Mice 0302 clinical medicine GSK-3 medicine Animals Pentylenetetrazol Rats Wistar seizure models Zebrafish Protein Kinase Inhibitors 030304 developmental biology 0303 health sciences biology fungi General Medicine Cell Biology biology.organism_classification medicine.disease Rats Mice Inbred C57BL Anticonvulsant chemistry Pilocarpine physiology Anticonvulsants Indirubin 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | ACS chemical neuroscience. 10(4) |
| ISSN: | 1948-7193 |
| Popis: | In view of the clinical need for new antiseizure drugs (ASDs) with novel modes of action, we used a zebrafish seizure model to screen the anticonvulsant activity of medicinal plants used by traditional healers in the Congo for the treatment of epilepsy, and identified a crude plant extract that inhibited pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. Zebrafish bioassay-guided fractionation of this anticonvulsant Fabaceae species, Indigofera arrecta, identified indirubin, a compound with known inhibitory activity of glycogen synthase kinase (GSK)-3, as the bioactive component. Indirubin, as well as the more potent and selective GSK-3 inhibitor 6-bromoindirubin-3'-oxime (BIO-acetoxime) were tested in zebrafish and rodent seizure assays. Both compounds revealed anticonvulsant activity in PTZ-treated zebrafish larvae, with electroencephalographic recordings revealing reduction of epileptiform discharges. Both indirubin and BIO-acetoxime also showed anticonvulsant activity in the pilocarpine rat model for limbic seizures and in the 6-Hz refractory seizure mouse model. Most interestingly, BIO-acetoxime also exhibited anticonvulsant actions in 6-Hz fully kindled mice. Our findings thus provide the first evidence for anticonvulsant activity of GSK-3 inhibition, thereby implicating GSK-3 as a potential therapeutic entry point for epilepsy. Our results also support the use of zebrafish bioassay-guided fractionation of antiepileptic medicinal plant extracts as an effective strategy for the discovery of new ASDs with novel mechanisms of action. |
| Databáze: | OpenAIRE |
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