Valproate and myoclonus.
Valproate exhibits potent antiepileptic and antimyoclonic activity in a number of clinical and experimental syndromes. The mechanism of action of valproate remains unknown, but several neurotransmitter systems are affected directly or indirectly by valproate administration. The levels of the serotonin precursor and the principal serotonin metabolite, tryptophan and 5-hydroxyindoleacetic acid, respectively, are elevated in rodent brain following the administration of anticonvulsant doses of valproate. However, the anticonvulsant action of valproate is preserved in mice pretreated with p-chlorophenylalanine, which depletes the brain levels of serotonin and serotonin metabolites. Valproate administration elevates the level of the inhibitory transmitter glycine in the urine and plasma of patients and experimental animals, and the hepatic glycine cleavage enzyme is inhibited by valproate. The cerebral glycine levels in rodents are not affected by valproate administration, and the inhibitory action of glycine on reticular neuron firing is not affected by iontophoretically applied valproate. Valproate exerts multiple effects on the inhibitory GABA transmitter system. Elevation in brain GABA level occurs in parallel with the anticonvulsant activity observed following valproate administration, and high levels of valproate inhibit the GABA-metabolizing enzymes GABA-T and SSADH and cause a reduction in the rate of GABA turnover. Valproate has no effect on GABA uptake, release, or binding to the GABA receptor complex. Iontophoretically applied valproate augments the inhibitory action of GABA on neuronal firing in a number of brain regions including the reticular formation. Excitatory amino acid antagonists have recently been shown to possess anticonvulsant and antimyoclonic activity in a number of animal models. The ability of these compounds to decrease the brain level of the excitatory transmitter aspartate is shared by valproate. The valproate-induced decrease in aspartate level is dose dependent and coincides with the period of anticonvulsant protection. There is also a strong correlation between the anticonvulsant potency of a number of valproate analogs and their ability to reduce cerebral aspartate levels.