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Teratogenic and anticonvulsant effects of zinc and copper valproate complexes in zebrafish

•Valproate organometallic complex increases antiseizure activity.•Cu(Valp)2Bipy produces an antiseizure effect with high toxicity.•Zn(Valp)2Bipy should be the most promising modification for future studies. Valproic acid (VPA) is an antiepileptic drug (AED) that has the broadest spectrum across all...

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Bibliographic Details
Published in:Epilepsy research 2018-01, Vol.139, p.171-179
Main Authors: Grünspan, Lauren D., Mussulini, Ben Hur M., Baggio, Suelen, dos Santos, Paulo R., Dumas, Françoise, Rico, Eduardo P., de Oliveira, Diogo L., Moura, Sidnei
Format: Article
Language:English
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Summary:•Valproate organometallic complex increases antiseizure activity.•Cu(Valp)2Bipy produces an antiseizure effect with high toxicity.•Zn(Valp)2Bipy should be the most promising modification for future studies. Valproic acid (VPA) is an antiepileptic drug (AED) that has the broadest spectrum across all types of seizures and epileptic syndromes. Unfortunately, approximately 30% of epileptic patients are refractory to the classical AED. Metal ions have been frequently incorporated into pharmaceuticals for therapeutic or diagnostic purposes and research. In this preliminary study, we assess the embryo toxicity and the anticonvulsant activity of 4 novel metallodrugs, with Zn+2 and Cu+2, a derivative of valproic acid and the N-donor ligand in an adult zebrafish epileptic seizure model induced by pentylenetetrazole. The most toxic complex was [Cu(Valp)2Bipy], in which the LC50 was 0.22 μM at 48 h post fertilization (HPF) and 0.12 μM at 96 HPF, followed by [Zn(Valp)2Bipy] (LC50 = 10 μM). These same metallodrugs ([Cu(Valp)2Bipy] 10 mM/kg and [Zn(Valp)2Bipy] 30 mM and 100 mM/kg) displayed superior activity, thus reducing the seizure intensity by approximately 20 times compared to sodium valproate (175 mM/kg). Overall, [Cu(Valp)2Bipy] showed the best anticonvulsant effects. However, because of the toxicity of copper, [Zn(Valp)2Bipy] is considered the most promising anticonvulsant for future studies.
ISSN:0920-1211
1872-6844
DOI:10.1016/j.eplepsyres.2018.01.005