**7. Ion channel modulators as antiepileptic drugs**

Many of the antiepileptic drugs on the market today exert strong effects on ionic currents. Sodium channel blockers were used in the treatment of epilepsy as early as in 1940, and since then several other sodium channel blockers have been developed. Carbamazepine, first introduced in 1968, stabilizes the inactive conformation of sodium channels and is widely used in the treatment of partial and generalized tonic-clonic seizures. Lamotrigine blocks sodium channels in a voltage- and use-dependent manner and is efficient for partial, absence, myoclonic and tonic-clonic seizures (Kwan et al., 2001). Drugs that potentiate GABA receptor function, such as benzodiazepines, have also been used as anticonvulsants for several years. These act by binding to the interface between the α and γ subunits of the GABAA receptor, resulting in allosteric activation of the receptor (Kwan et al., 2001). Several established and novel antiepileptic drugs have been reported to act on various K+ currents, but none of them exert their main effect on potassium channels (Meldrum and Rogawski, 2007). Carbamazepine also exerts an effect on nAChRs by blocking the open conformation of the channel and is very effective in treatment of patients with ADNFLE. This effect might be related to the fact that several of the disease causing mutations in CHRNA4 and CHRNA2 increase the sensitivity to the drug (Ortells and Barrantes, 2002).

The knowledge of how mutations in ion channels cause neuronal hyperexcitability and epilepsy has led to new therapeutic strategies for prevention of seizures. The mutated proteins serve as mechanistic proof of concept that pharmacological antagonization of the epilepsy causing mechanisms could have desirable effects on neuronal excitability. These mechanisms are not necessarily targeted for treatment of the respective epilepsy syndrome, but as they are showed to cause hyperexcitability in the affected patients, antagonizing drugs may reduce excitability in patients with other types of epilepsy. An excellent example of this is Retigabine (other names are Trobalt, Potiga, or Ezogabine), which was approved by both the European Medicines Agency and the U.S. Food and Drug Administration in 2011 as adjunctive treatment for partial onset seizures. It was originally synthesized as a GABA modulator, but it was later shown that its main molecular target is the neuronal Kv7 channels (Main et al., 2000; Rundfeldt and Netzer, 2000; Wickenden et al., 2000). Retigabine induces a large hyperpolarizing shift in the voltage-dependence of activation of Kv7 channels, accelerates the activation kinetics and slows deactivation kinetics. Enhancement of M-current would clearly be effective in prevention of seizures in BNFC patients, but mutations in the Kv7 channels might render them insensitive to such drugs, which hampers the use of Kv7 channel openers in the treatment of BNFC. The hypothesis of reduced NaV1.1 current in the pathogenesis of GEFS+ and SMEI, together with its primary expression in inhibitory interneurons, indicates that this sodium channel subtype plays a role in reducing neuronal excitability (Ogiwara et al., 2007; Yu et al., 2006). This opens the intriguing possibility that selective NaV1.1 openers can function as anticonvulsants, even though sodium channel openers generally are known as epileptogenic substances.

An understanding of the etiology of the epilepsy syndromes and the causal factors in individual patients are also critical for selection of the right medication. Sodium channel blockers, which normally would exhibit anticonvulsant properties, would clearly not be the right choice to treat patients with SMEI, where a lack of sodium current seems to be the underlying cause. Similarly, as too much inhibition seems to play a role in the pathogenesis

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### **8. Conclusion**

As about 30% of all patients with epilepsy respond poorly to antiepileptic drugs, there is clearly a need for development of new therapies. The growing understanding of the epileptic channelopathies and the structural and functional characterization of the mutated channels provide several opportunities for creation of novel and improved drugs.
