N. Lindekens et al., In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy, PHARM RES, 17(11), 2000, pp. 1408-1413
Purpose. We evaluated the effectiveness of the commonly used antiepileptic
drug sodium valproate (400 mg/kg) and two of its amide derivatives, valprom
ide and valnoctamide (both 100 mg/kg), in an in vivo rat model of focal epi
lepsy. Our main interest was to get insight into possible changes in extrac
ellular amino acid neurotransmitter levels following administration of the
drugs, both in control and in epileptic conditions.
Methods: Seizures were evoked in freely moving rats by intrahippocampal adm
inistration of pilocarpine via a microdialysis probe (10 mM for 40 min at 2
mul/min). Microdialysis was also used as bl vivo sampling technique and al
terations in extracellular hippocampal glutamate and GABA levels were monit
ored. Electrophysiological evidence for the presence or absence of seizures
was simultaneously recorded with electrocorticography.
Results. The focally evoked pilocarpine-induced seizures were completely pr
evented by acute intraperitoneal pretreatment with each of the three drugs
in the respective doses. Effective protection was reflected in the electroc
orticographic recordings and in the lack of sustained elevations of the ext
racellular glutamate levels after pilocarpine perfusion. Little effects wer
e seen on the basal extracellular amino acid levels after systemic administ
ration of each of the compounds, nor after the intrahippocampal administrat
ion of sodium valproate.
Conclusions. Valnoctamide and valpromide (100 mg/kg) proved to be at least
as effective as their parent compound sodium valproate (400 mg/kg) against
pilocarpine-induced seizures. All three compounds however failed to induce
significant initial alterations in extracellular hippocampal GABA release.
This questions the enhance ment of GABA-mediated inhibition as bring one of
their mechanisms of action.