Study on the mechanisms of anticonvulsant acivity of (N-Hydroxymethyl)-2-propylpentamide

Abstract

The purposes of the present study were to study the anticonvulsant mechanisms of N- Hydroxymethyl-2-propylpentamide (HPP), a newly synthesized valproic analogue with anticonvulsant activity, on the level of brain amino acid neurotransmitters of freely moving rats. Changes of brain amino acid namely, glutamate, aspartate, glycine and GABA (gamma-aminobutyric acid) were investigated by microdialysis technique. Furthermore, the effects of this compound on GABA[subscript A], glycine and NMDA (N- methyl-D-aspartate) receptors in acutely dissociated rat hippocampal neurons using the whole-cell application of the patch-clamp techniques was also investigated. Significant decreases in the level of cortical glutamate, an excitatory amino acid neurotransmitter, was noted in both of HPP-treated groups whereas a reduction of glutamate was observed only in rats receiving high dose (440 mg/kg B.W.) of VPA. However, HPP did not directly elicite inward currents in acutely dissociated rat hippocampal neurons. Additionally, GABA[subscript A], glycine and NMDA currents were unaltered by HPP. Thus it is highly likely that a decrease in brain glutamate could primarily account for anticonvulsant effect of HPP observed in rats. Based on our finding that VPA in the dose of 440 but not 220 mg/kg B.W. exclusively decreased the level of brain glutamate, it could be concluded hereby that HPP possessed the same mechanism of anticonvulsant activity as that exhibited by VPA but much stronger. A decrease in cortical glutamate seemed to be a primary anticonvulsant mechanism of HPP. Some mechanisms other than that demonstrated in the present study should be further investigated.