New hope for the treatment of epilepsy.

Compared to many other chronic neurological diseases, epilepsy can be regarded as relatively amenable to treatment, given that about two-thirds of patients become seizure-free with available medications. However, there are two major problems with current treatment using antiepileptic drugs. First, about one-third of patients with epilepsy are resistant to the available antiepileptic drugs, and second, the treatment is purely ‘symptomatic’, i.e. when the drugs are stopped, epileptic seizures usually recur, as the underlying cause of the seizures is still present. Epileptogenesis describes the process of development of epilepsy after an initial brain insult, such as trauma or a prolonged febrile seizure (Fig. 1) (Pitkänen and Lukasiuk, 2011). However, there are currently no treatments that target the process of epileptogenesis in an effort to prevent or at least modify the disease. There is only one possibility to cure epilepsy, namely epilepsy surgery, a treatment that can only be applied to selected patients in whom the epileptic focus can be surgically removed. Thus, new therapeutic approaches are urgently needed. In this issue of Brain, Doeser et al. (2014a) report that an existing AED, eslicarbazepine acetate (ESL), has unexpected effects with the potential to address both pharmacoresistance and epileptogenesis. ESL is a derivative of the long-established drug carbamazepine (CBZ) and its first modification oxcarbazepine (OXC). Toxic epoxides are not formed from ESL, and unlike OXC, which is converted into both eslicarbazepine (S-Lic) and (R)-licarbazepine, ESL is mainly converted to S-Lic. Based on these chemical properties, ESL has been developed for clinical use mainly to improve tolerability by reducing side effects of CBZ and OXC. Only recently, it has been reported that the effects these drugs exert on sodium channels seem to differ (Hebeisen et al., 2014). Doeser et al. (2014a) now present two major novel findings concerning S-Lic/ESL. First, S-Lic has additional efficacy over CBZ in vitro in hippocampal brain slices from (i) pharmacoresistant patients with mesial temporal lobe epilepsy (TLE) who underwent epilepsy surgery with resection of the hippocampus; and (ii) a rat model of mesial TLE. Second, they observed an anti-epileptogenic, disease-modifying effect of ESL when the drug was administered early in the course of development of epilepsy in a mouse model. The authors describe an additional, previously unknown, mechanism of action of S-Lic that may explain this anti-epileptogenic activity. More than 10 years ago, the group of Heinz Beck first described a correlation between the clinical response to CBZ in patients and the in vitro effect of CBZ on hippocampal brain slices obtained from the same patients. They were able to reproduce this finding in the rat pilocarpine model of mesial TLE (Remy et al., 2003). Interestingly, the difference in the effect of CBZ in pharmacoresistant and (partially) pharmacoresponsive cases was restricted to a single property of voltage-gated sodium channels—the target of CBZ, OXC and S-Lic— namely, the recovery from fast inactivation. In another study, the same group found evidence that the sodium channel b1-subunit, a smaller subunit which has modifying effects on the main -subunits, modifies CBZ-sensitivity of persistent sodium currents, but this could not explain altered effects of CBZ on the recovery from fast inactivation (Uebachs et al., 2010). They also showed later on that the drug effect of S-Lic is not influenced by loss of the b1-subunit (Doeser et al., 2014b). Doeser et al. (2014a) have now examined the effects of S-Lic (applied to brain slices) and ESL (administered to mice) in human and rodent mesial TLE. The authors’ experiments were guided by clinical studies that showed evidence for additional beneficial effects of ESL, also in CBZ-resistant patients (Elger et al., 2009). Those results were surprising and went unexplained at the time, since the same mechanism of action was initially presumed for both drugs. When Doeser and colleagues (2014a) applied S-Lic in addition to CBZ to hippocampal brain slices of CBZ-resistant patients or rats, they observed that S-Lic was able to overcome the CBZ-resistance on recovery from fast inactivation, as S-Lic potently slowed the recovery process. Interestingly, this add-on effect of S-Lic to CBZ was restricted to recovery from fast inactivation; S-Lic did not add to the effects of CBZ on other properties of sodium currents. S-Lic alone also had clear effects on various properties of sodium currents, but these did not differ between epileptic animals and non-epileptic controls. When added to CBZ, S-Lic also produced an additional reduction in repetitive neuronal firing in human brain slices. For unknown reasons, this latter add-on effect of S-Lic to CBZ could not be reproduced in the pilocarpine model. Doeser et al. (2014a) further discovered that S-Lic has an additional mechanism of action on another ion channel, the T-type calcium channel CaV3.2. This channel plays an important role in epileptogenesis, because this process is largely inhibited in CaV3.2 knock-out mice (Becker et al., 2008). These observations triggered another series of experiments in which Doeser and colleagues examined whether ESL exhibits anti-epileptogenic effects in the mouse pilocarpine model of mesial TLE. After inducing status epilepticus with pilocarpine, they applied ESL or vehicle for 6 weeks in two dosages adapted from pharmacokinetic data 240 | BRAIN 2015: 138; 238–245 Scientific Commentaries