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

Abstract

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.

Keywords: Anticonvulsant; Pentylenetetrazole; Teratogenic; Valproate complex; Zebrafish.