Identification of GSK-3 as a Potential Therapeutic Entry Point for Epilepsy.

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.

• Authors: 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
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 10 Issue 4 Pg. 1992-2003 (04 17 2019) ISSN: 1948-7193 [Electronic] United States
• PMID: 30351911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Indoles
• Protein Kinase Inhibitors
• Glycogen Synthase Kinase 3
• indirubin

Topics

• Animals
• Anticonvulsants (pharmacology, therapeutic use)
• Epilepsy (drug therapy, enzymology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Indoles (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Zebrafish