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

Aourz, Najat and Serruys, Ann-Sophie K. and Chabwine, Joëlle N. and Balegamire, Pascal Byenda and Afrikanova, Tatiana and Edrada-Ebel, RuAngelie and Grey, Alexander I. and Kamuhabwa, Appolinary R. and Walrave, Laura and Esguerra, Camila V. and van Leuven, Fred and de Witte, Peter A. M. and Smolders, Ilse and Crawford, Alexander D. (2018) Identification of GSK-3 as a potential therapeutic entry point for epilepsy. ACS Chemical Neuroscience. ISSN 1948-7193

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    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.