Mechanisms of Action of Antiepileptic Drugs

Cultures of mammalian CNS have played a critical role in our modern understanding of the cellular and molecular mechanisms of antiepileptic drugs. Almost all the currently available AEDs were developed based on animal screening models. The mechanisms of action of these drugs were completely unknown when the drugs were introduced, and to some extent these mechanisms remain unknown for several important "old" and "new" AEDs. However, we have a sophisticated understanding of the mechanisms by which many of our currently used AEDs work.

Sodium Channel Blockers

Several very potent AEDs have as a primary mechanism of action the ability to block voltage-dependent Na channels in a voltage- or use-dependent fashion. Using preparations of mammalian spinal cord or cortical cell cultures, several groups demonstrated that phenytoin, carbamazepine, lamot-rigine, and zonisamide could block sustained repetitive firing (SRS) in neurons as induced by prolonged depolarizing current pulses (Macdonald and McLean, 1982; Macdonald et al., 1985). Early action potentials in the train were generally minimally affected, but as the neurons remained depolarized, the drugs were able increasingly to block more and more channels. Subsequent voltage-clamp experiments demonstrated the voltage-dependent nature of the block.

GABA Receptor Complex Allosteric Modulators

Several of our more commonly employed AEDs work as allosteric modulators of the GABA receptor complex (GRC), mechanisms first elucidated by studies of cell cultures. Benzodiazepines enhance the affinity of GABA at the receptor and allow enhanced channel openings (Macdonald et al., 1986); barbiturates prolong channel openings and can produce channel openings even in the absence of GABA (Macdonald et al., 1988). Topirimate also appears to enhance GABA-mediated inhibition (White et al., 1997, 2000).

GABA Uptake Inhibitors

Tiagabine was developed as an inhibitor of GABA uptake. It was hypothesized that such inhibition would result in more GABA extracellularly, and thus there would be enhanced inhibition. Studies in cell culture have produced evidence that this assumption may reflect an oversimplification of the processes involved. In the cell culture system, enhanced GABA at the synapse may not produce stronger inhibition, either at GABAa or GABAb receptors. Paradoxically the increased GABA primarily affects presynaptic GABAB receptors on interneurons and therefore downregu-lates GABA release, thereby producing less inhibition (Oh and Dichter, 1994). This surprising result may account for the complex response of some seizure types to tiagabine. This drug appears to exacerbate absence-like seizures and possibly some forms of status epilepticus, but it reduces partial seizures (Eckardt and Steinhoff, 1998; Ettinger et al., 1999; Fitzek et al., 2001; Genton, 2000; Knake et al., 1999; Piccinelli et al., 2000; Schapel and Chadwick, 1996; Shinnar et al., 2001; Skardoutsou et al., 2003; Skodda et al., 2001; Solomon and Labar, 1998; Steinhoff and Eckardt, 1999).

Similarly complex results were obtained when analyzing the effects of glutamate transport inhibitors on excitatory synaptic physiology. Instead of simply enhancing excitation, these agents often dampened excitatory synapses by an action of the excess synaptic glutamate on presynaptic metabotropic glutamate receptors (mGluRs), which decreased transmitter release from excitatory terminals (Maki et al., 1994).

Glutamate Receptor Antagonists

It has been hypothesized that antagonists of either the AMPA or NMDA receptor subtype could be effective AEDs—if such antagonism were not too toxic. Many of the drugs that work as antagonists at these receptors were developed and characterized using a CNS cell culture system. So far, however, drugs that target these receptors have not been as useful as hoped, partly because of toxicity and partly because of limited efficacy. One of the new AEDs, topiramate, has been shown to act by blocking kainate receptors (Gibbs et al., 2000; Gryder and Rogawski, 2003) in addition to its effect on GABA receptors. This type of multiple targeting, with drugs that affect multiple receptor (or channel) types, may prove to be a new avenue for AED development. Other drugs that act as weak noncompetitive antagonists at AMPA or NMDA receptors are being developed, and these may prove to be more effective than the earlier compounds tested (Rogawski, 2000; Donevan and Rogawski, 2000).

Potassium Channel Modulators

Another new class of possible AEDs is being developed based on a mechanism that was first demonstrated in CNS cell cultures. These agents enhance the opening of subclasses of voltage-dependent K channels or in some cases open the channels directly. The net effect is to dampen neuronal excitability.

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