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In view of the clinical need for new anti-epileptic drugs (AEDs) with novel modes of action, we used a zebrafish seizure model to screen the anticonvulsant activity of medicinal plants used for traditional epilepsy treatment in the Congo, identifying 4 crude plant extracts that inhibited pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. Zebrafish bioassay-guided fractionation of an anticonvulsant Fabaceae species, Indigofera arrecta, identified indirubin, an bis-indole alkaloid with known inhibitory activity at glycogen synthase kinase (GSK)-3, a well known protein kinase. Target validation experiments with partial loss of function of GSK-3 via antisense knockdown in zebrafish showed anticvonvulant activity against PTZ-induced seizures. Subsequently, indirubin, together with the more potent and GSK-3 specific derivative 6-bromoindirubin-3'-oxime (BIOacetoxime) and the structurally unrelated GSK-3β inhibitor 2-methyl-5-[3-[4-(methylsulfinyl)phenyl]-5-benzofuranyl]-1,3,4-oxadiazole (TCS2002), were tested in zebrafish and rodent seizure assays. All 3 compounds revealed anticonvulsant activity in PTZ-treated zebrafish larvae, with electroencephalographic recordings revealing reduction of epileptiform discharges. All 3 compounds also showed anticonvulsant activity in the pilocarpine rat model for limbic seizures and in the 6-Hz psychomotor refractory seizure mouse model. Moreover, BIOacetoxime, the most potent GSK-3 inhibitor was also able to exert anticonvulsant actions in 6-Hz fully kindled mice. Our findings provide the first evidence for anticonvulsant activity of selective GSK-3 inhibitors, thereby implicating GSK-3 as a potential new drug target 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 AEDs with novel mechanisms of action.

Introduction Little is known about the outcomes of subjects with a history of severe acute malnutrition (SAM). We therefore sought to explore the long-term effects of SAM during childhood on human capital in adulthood in terms of education, cognition, self-esteem and health-related disabilities in daily living. Methodology We traced 524 adults (median age of 22) in the eastern Democratic Republic of the Congo, who were treated for SAM during childhood at Lwiro hospital between 1988 and 2007 (median age 41 months). We compared them with 407 community controls of comparable age and sex. Our outcomes of interest were education, cognitive function [assessed using the Mini Mental State Examination (MMSE) for literate participants, or its modified version created by Ertan et al. (MMSE-I) for uneducated participants], self-esteem (measured using the Rosenberg Self-Esteem Scale) and health-related social and functional disabilities measured using the World Health Organization Disability Assessment Schedule (WHODAS). For comparison, we used the Chi-squared test along with the Student’s t-test for the proportions and means respectively. Results Compared with the community controls, malnutrition survivors had a lower probability of attaining a high level of education (p < 0.001), of reporting a high academic performance (p = 0.014) or of having high self-esteem (p = 0.003). In addition, malnutrition survivors had an overall mean score in the cognitive test that was lower compared with the community controls [25.6 compared with 27.8, p = 0.001 (MMSE) and 22.8 compared with 26.3, p < 0.001(MMSE-I)] and a lower proportion of subjects with a normal result in this test (78.0% compared with 90.1%, p < 0.001). Lastly, in terms of health-related disabilities, unlike the community controls, malnutrition survivors had less social disability (p = 0.034), but no difference was observed as regards activities of daily living (p = 0.322). Conclusion SAM during childhood exposes survivors to low human capital as regards education, cognition and behaviour in adulthood. Policy-deciders seeking to promote economic growth and to address various psychological and medico-social disorders must take into consideration the fact that appropriate investment in child health as regards SAM is an essential means to achieve this.