Effect of newly synthesized valproic analogues, valproyl hydroxamic acid (VHA) was investigated in comparing to valproic acid (VPA) on cerebellar Purkinje neurons by microiontophoretic techniques. VHA and VPA depressed spontaneous firing of cerebellar Purkinje neurons. Furthermore, we examined the effect of microiontophoretically applied VHA in comparing to VPA on neuronal response to inhibitory amino acids neurotransmitters (GABA, glycine) and excitatory amino acids neurotransmitters (glutamate and aspartate). It was found that VHA enhanced the inhibition of GABA without showing any appreciable effect on the inhibition of glycine and the excitation of both glutamate and aspartate. The effects were similar to those of VPA which potentiated the GABA responses while not affecting the response of glycine, glutamate and aspartate. These results suggested that VHA exerted anticonvulsant activity by mechanism similar to those of VPA. The direct effect of VHA and VPA on GABA[subscriptA] or glycine receptor was further probed by their respective receptor antagonists (bicuculline and strychnine). In these studies, we found that bicuculline and strychnine antagonized the depressant effect of VHA, while bicuculline and strychnine had no effect on the depressant effect of VPA. The effect of VHA was previously reported to be effective in bicuculline-induced convulsion and rather ineffective (high ED[subscript50]value) instrychnine-induced convulsion in whole animal model. Based on our finding that bicuculline and strychnine antagonized the depressant effect of VHA. It could be concluded hereby that GABA[subscriptA] receptor mediated inhibition seemed to be a principal anticonvulsant action of VHA whereas glycine receptor mediated inhibition could be part of its anticonvulsant action in concert with other undefined mechanism.
