PUBLICATION
Identification of GSK-3 as a potential therapeutic entry point for epilepsy
- Authors
- Aourz, N., Serruys, A.K., Chabwine, J., Balegamire, P.B., Afrikanova, T., Edrada-Ebel, R., Gray, A.I., Kamuhabwa, A.R., Walrave, L., Esguerra, C.V., van Leuven, F., de Witte, P.A.M., Smolders, I., Crawford, A.D.
- ID
- ZDB-PUB-181024-10
- Date
- 2018
- Source
- ACS Chemical Neuroscience 10(4): 1992-2003 (Journal)
- Registered Authors
- Crawford, Alexander, Esguerra, Camila V.
- Keywords
- none
- MeSH Terms
-
- Animals
- Anticonvulsants/pharmacology
- Anticonvulsants/therapeutic use*
- Epilepsy/drug therapy*
- Epilepsy/enzymology*
- Glycogen Synthase Kinase 3/antagonists & inhibitors*
- Glycogen Synthase Kinase 3/metabolism*
- Indoles/pharmacology
- Indoles/therapeutic use
- Male
- Mice
- Mice, Inbred C57BL
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use*
- Rats
- Rats, Wistar
- Zebrafish
- PubMed
- 30351911 Full text @ ACS Chem. Neurosci.
Citation
Aourz, N., Serruys, A.K., Chabwine, J., Balegamire, P.B., Afrikanova, T., Edrada-Ebel, R., Gray, A.I., Kamuhabwa, A.R., Walrave, L., Esguerra, C.V., van Leuven, F., de Witte, P.A.M., Smolders, I., Crawford, A.D. (2018) Identification of GSK-3 as a potential therapeutic entry point for epilepsy. ACS Chemical Neuroscience. 10(4):1992-2003.
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 plantsused 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, Indigoferaarrecta, identified indirubin, a compound with known inhibitory activity ofglycogen synthase kinase 3 (GSK-3), as the bioactive component.Indirubin, as well asthe 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-acetoximealso 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-Hzfully kindled mice. Our findings thus provide the first evidence for anticonvulsant activity of GSK-3inhibition,thereby implicating GSK-3 as a potential therapeutic entry point for epilepsy.Our results also support the use of zebrafish bioassay-guided fractionation of anti-epileptic medicinal plant extracts as an effective strategy for the discovery of new ASDs with novel mechanisms of action.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping