There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the "ethosuximide is a T-type calcium channel blocker" gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

In March of 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca²⁺ currents in T-type Ca²⁺ channels in freshly removed thalamic neurons. In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al in 1992, who reported a substantial reduction in current in dorsal root ganglia at concentrations ranging from 7 μM to 1 mM.

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mM. The year after, a study conducted on human neocortical cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca²⁺ currents at the concentrations typically needed for a therapeutic effect.

In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mM&mdashfar higher than Kostyuk reported. That same year, Leresche et al reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na⁺ current by 60% and the Ca²⁺-activated K⁺ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na⁺ current is responsible for the anti-absence properties.

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Drugs lengthen worm's life span
From Science News, 2/5/05

A class of antiseizure drugs slows aging and increases life span in the roundworm Coenorhabditis elegans, researchers have found.

Because C. elegans has a naturally short life span--about 2 weeks, on average--scientists frequently use the species to explore aging. Previous studies have identified genetic modifications that can increase the worms' life span. However, few studies have examined whether drugs might have a life-extending effect as well, says Kerry Kornfeld of the Washington University School of Medicine in St. Louis.

He and his colleagues dosed separate groups of the worms with various types of drugs, ranging from diuretics to anti-depressants. Although most of the drugs had no effect or were toxic to the worms, Kornfeld's team found that ethosuximide, an anticonvulsant drug, increased the worms' life span by 17 percent.

A chemically related drug, trimethadione, extended the worms' lives by a whopping 47 percent, the team reports in the Jan. 14 Science.

The anticonvulsant drugs increased the worms' motility and stimulated egg laying, suggesting that the chemicals interact with C. elegans' nervous system. Kornfeld and his colleagues are now investigating whether the drugs deliver their life-extending effects by acting on still-to-be-discovered nerve cell processes that regulate aging.

Despite the boost in longevity that the anticonvulsant drugs yielded in worms, Kornfeld cautions that a similar effect has not been documented in people.

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