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The mechanism of action of sodium valproate

1981; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês

10.1016/0306-3623(81)90101-4

1879-0011

R. Kerwin, Peter V. Taberner,

Enzyme function and inhibition

Sodium valproate (Zpropylvalerate sodium, di-n-propylacetate sodium) is a broad spectrum anticonvulsant marketed under the names of Epilim, Depakine, Ergenyl etc. and which has proved useful in the treatment of most types of epilepsy and particularly absence seizures which are often refractory to alternative therapy. Its anticonvulsant properties were first recognized in France by Meunier et al. (1963) who were using di-n-propylacetic acid as a vehicle for the administration of a series of other anticonvulsant drugs. It has been in use clinically in Europe for about 10 years and has recently been approved by the United States Food and Drug Administration authorities for the treatment of absence seizures (Browne, 1980). The clinical properties of valproate have been extensively reviewed (Pinder et al., 1977; Browne, 1980), but pharmacological interest in the drug has arisen mainly as a result of the ability of valproate to raise brain y-aminobutyric acid (GABA) levels (Godin et al., 1969). Since GABA has become established as a major inhibitory transmitter in the brain, the inherent potential of the manipulation of GABA metabolism in order to obtain an anticonvulsant or anti-epileptic effect has stimulated wide interest (see, for example Meldrum, 1979). In fact, much of the indirect evidence for the transmitter role of GABA has derived from studies in which inhibitors of GABA-aminotransferase (GABA-T, EC 2.6.1.19), the enzyme responsible for the inactivation of GABA have been shown to be anticonvulsant. However, in order to postulate a role for GABA in the anticonvulsant effect of a drug it is necessary to satisfy three criteria, namely: