Effects of various valproic acid derivatives on low-calcium spontaneous epileptiform activity in hippocampal slices

Lowering of extracellular calcium induces the development of spontaneous epileptiform activities in rat hippocampal slices. The antiepileptogenic effect of four new sugar-ester derivatives of valproic acid--dimethylenexylitol valproate, monoacetoneglucose valproate, diacetoneglucose valproate and glucose valproate--were investigated on such activity through 20-min bath applications and their effect compared to that of valproate, valpromide and phenytoin. Sodium valproate, 5 mM, did not completely suppress the spontaneous epileptiform activity. Valpromide, 2.5 mM, and phenytoin, 0.25 mM, produced complete cessation of seizure activity. Dimethylenexylitol valproate, 0.1 mM, completely suppressed spontaneous epileptiform activities. The other derivatives were less potent: concentrations of 0.25 mM of monoacetoneglucose valproate and 1 mM of diacetoneglucose valproate and glucose valproate were required for complete cessation of activity. The sugar carriers alone were devoid of effect. The data show that these molecules have a direct action on the nervous tissue and their antiepileptogenic efficacy in the low-calcium model is far larger than that of valproic acid itself. Such derivatives, especially dimethylenexylitol valproate, appear to be promising for development of new antiepileptic molecules.