Identification of GSK-3 as a Potential Therapeutic Entry Point for Epilepsy.
ACS Chem Neurosci
; 10(4): 1992-2003, 2019 04 17.
Article
en En
| MEDLINE
| ID: mdl-30351911
ABSTRACT
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Glucógeno Sintasa Quinasa 3
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Inhibidores de Proteínas Quinasas
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Epilepsia
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Anticonvulsivantes
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Idioma:
En
Revista:
ACS Chem Neurosci
Año:
2019
Tipo del documento:
Article
País de afiliación:
Bélgica