Valproic acid (VPA) has multiple mechanisms of action; this is not in dispute.

We were teaching didactics from Wyllie the other day and noted their section on VPA says “Similarly, despite efficacy in absence epilepsy, there is little support for effects on T-type calcium channels.”

This was surprising to me.

Way back in 1990 Kelly et al. did experiments showing reductions in the peak T current, the low-threshold calcium currents mediated by T-type calcium channels (TCCs), at “clinically relevant concentrations.” It had “no effect on the high-threshold (N and L) current components.” Crucially this study was conducted in rat nodose ganglion neurons.

Tringham et al. in 2012 tested multiple compounds for activity against TCCs and compared to ethosuximide (ETX) and VPA in HEK cells expressing TCCs. VPA had an IC50 of 190 mM.

Complicating the picture is Heady et al. 2000 in their review of TCC molecular pharmacology notes that VPA only incompletely blocks TCCs in various parts of the brain and apparently has no effect in the ventrobasal thalamus. That said this review didn’t have data about TCC block in the reticular nucleus, which is believed to be ground zero for centrencephalic absences.

Before the Kelly et al. paper in 1989 Coulter et al. used voltage-clamp techniques to investigate the T current and ETX in “acutely isolated ventrobasal complex neurons from rats and guinea pigs.” ETX and dimethadione reduced T currents; valproate had “no effect.” This would seem to be consistent with other studies’ findings of differential TCC effects of VPA that depend on the neuronal site.

VPA did inhibit T currents in WAG/Rij rat thalamocortical relay neurons but at concentrations of 1 mM which is noted to be above the clinically relevant CSF concentration [weisskoschak][(Pathologies of Calcium Channels, chapter 4)]. [Sayer et al. 1993][sayer] noted previously that at therapeutic concentrations neither VPA nor ETX inhibited T currents in acutely isolated human temporal neocortical cells.

What is the upside to all of this? It looks like VPA can inhibit T currents but does so to different degrees depending on the site within the brain and probably has inferior effects to ETX. The picture is, indeed, more complex than I imagined—though personally I would not have written that there was “little support” for its effects as the textbook says.