Effect of valproyl hydroxamic acid on cortical amino acid neurotransmitters in rats

Abstract

The purposes of the present study were to study the effects of valproyl hydroxamic acid (VHA), a newly synthesized valproic analogue with anticonvulsant activity, on the level of brain amino acid neurotransmitters of freely moving rats. The maximal electroshock seizure (MES) test was used to determine the median effect dose (ED50) of VHA. Changes of brain amino acid namely, glutamate, aspartate, glycine and GABA were investigated by microdialysis technique. The ED50 of VHA to protect rats against MES test was found to be 80 (51-124) mg/kg B.w. Thus the effects of VHA in the dose of 100 and 200 mg/kg B.w. were further investigated in freely moving rats. Significant increases in the level of cortical glycine, an inhibitory amino acid neurotransmitter, were noted in both of VHA-treated group whereas an increment of GABA was observed only in rats receiving high dose (200 mg/kg B.w.) of VHA. Thus it is highly likely that an increase in brain glycine could primarily account for anticonvulsant effect of VHA observed in rats. In addition the effect of VHA on GABA which is a major inhibitory brain amino acid could also play role when high dose of VHA was used. Based on our finding that valproic acid (VPA) in the dose of 400 but not 200 mg/kg B.w. exclusively decreased the level of brain glutamate, it could be concluded hereby that VHA possessed different mechanism of anticonvulsant activity from that exhibited by VPA. An increase in cortical glycine seemed to be a primary anticonvulsant mechanism of VHA whereas an increment of GABA could take part as well if higher dose of VHA was used. Some mechanisms other than those demonstrated in the present study should be further investigated.