Identification of GSK-3 as a potential therapeutic entry point for epilepsy

Najat Aourz, Ann-Sophie K. Serruys, Joëlle N. Chabwine, Pascal Byenda Balegamire, Tatiana Afrikanova, RuAngelie Edrada-Ebel, Alexander I. Grey, Appolinary R. Kamuhabwa, Laura Walrave, Camila V. Esguerra, Fred van Leuven, Peter A. M. de Witte, Ilse Smolders, Alexander D. Crawford

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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.

Original languageEnglish
Pages (from-to)1992-2003
Number of pages12
JournalACS Chemical Neuroscience
Issue number4
Early online date23 Oct 2018
Publication statusPublished - 17 Apr 2019


  • 6Hz
  • epilepsy
  • GSK-3
  • indirubin
  • seizure models
  • zebrafish


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