Mechanisms of action of valproate: a commentatory

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Abstract

Valproate, one of the major antiepileptic drugs used today, has besides its wide use in both generalized and partial epilepsies, several new approved indications including the treatment of bipolar disorders, neuropathic pain, and as a migraine prophylaxis. This wide spectrum of activities is reflected by several different mechanisms of action, which are discussed in this review.

With regard to the antiepileptic effect of VPA, a special emphasis is put on the effect on the GABAergic system and the effect on enzymes like succinate semialdehyde dehydrogenase (SSA-DH), GABA transaminase (GABA-T), and α-ketoglutarate dehydrogenase, related to the tricarboxylic acid (TCA) cycle and thereby cerebral metabolism. In vitro studies have shown that VPA is a potent inhibitor of SSA-DH. In brain homogenates, GABA-T is inhibited at high concentrations only. Besides affecting the GABA-shunt, VPA might also inhibit the TCA cycle at the α-ketoglutarate dehydrogenase step.

The effect of VPA on excitatory neurotransmission and on excitatory membranes are mechanisms likely to be responsible for the ‘mood-stabilizing’ effect as well as in the treatment of migraine. GABA-mediated responses may be involved in neuropathic pain. But still there are many aspects of the mechanisms of action of VPA that remain unknown.

Section snippets

Background

Valproic acid (sodium valproate, VPA) is the most commonly used antiepileptic drug today in the treatment of generalized epilepsy, and it is also effective in partial epilepsy. In spite of its wide use for many years, the mechanism of VPA action is still not fully understood. Its simple structure of a short-branched fatty acid differs to a great extent from the substituted heterocyclic ring structures characterizing the traditionally used antiepileptic drugs. The antiepileptic action of VPA is

Effects on GABA levels

Attention has also been focused on the modification of the main inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA) by VPA. Impairment of GABAergic inhibitory neurotransmission can lead to convulsions, whereas potentiation of GABAergic activity results in anticonvulsant effects (Löscher, 1989). Favoring the GABAergic hypothesis for VPA, is inhibition of the onset of seizures induced by GABA antagonists (Frey and Löscher, 1976). VPA selectively enhances GABAergic inhibition in

Effects on enzymes related to the metabolic pathways of GABA and cerebral metabolism

The effects of VPA on enzymes are usually not discussed to any extent in reviews on antiepileptic drugs. VPA has, however, been shown to affect several enzymes connected to the synthesis and degradation of GABA and metabolites. It should be kept in mind, that assumptions made from early in vitro studies on brain concentrations are misleading, since VPA is not equally distributed in the body, but the plasma/brain ratio is 0.15–0.2 (Löscher, 1993). Also it is an important notion that the half

Effects on sodium channels

The predominant mechanism of action of VPA described in the literature is its action on ion channels, like the other traditionally used anticonvulsive agents (phenytoin and carbamazepine). VPA appears to act at the voltage-dependent Na+-channel, inhibiting high-frequency firing of neurons (McLean and MacDonald, 1986, Thomas et al., 1996). A rapid and sustained reduction in the firing rate of reticular neurons has been described after treatment with VPA 200 mg/kg in the rat (Farrant and Webster,

Effects on other neurotransmitters

Another mechanism which would also result in a lowered excitatory neurotransmission, is an action on excitatory neurotransmitters. Some studies have suggested that VPA causes decreased excitatory transmission in brain: VPA acts by reducing the number of action potentials elicted by application of NMDA in neocortical neurons in the rat at concentrations <1 mM (Zeise et al., 1991). In amygdaloid slices VPA in a dose related manner suppressed the response mediated by NMDA receptors (Gean, 1994).

New applications for valproate

During the last years, several new applications for valproate in psychiatry and neurology have been proved in preclinical and clinical studies. Its different mechanisms of action contribute to the broad spectrum of activity for VPA: its mood-stabilizing effect through preventing hyperexcitability in membranes via inhibiting voltage activated sodium channels, its action on excitatory neurotransmitters, or its various GABAergic actions.

Conclusion

Valproate is one of the most used anticonvulsants and is also now used in the treatment of psychiatric disorders. Its mechanism of action is, however, not fully understood. VPA increases GABA levels probably by increasing succinic semialdehyde, a good endogenous inhibitor of GABA-T. Evidence has emerged that valproate exerts a direct effect on excitable membranes and also attenuates the NMDA receptor channel. The action of valproate may therefore be exerted through several different mechanisms

Acknowledgements

I am grateful to Professor dr. Frode Fonnum for helpful discussions and advice when writing this manuscript.

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