Abstracts

Rationale: The search for antiepileptic drugs to help patients with drug-resistant epilepsies is still an ongoing endeavour. Slices obtained from epilepsy resection surgeries provide a platform to evaluate the effects of newly proposed agents, despite the low throughput of these experiments due to their dependence on surgical tissue availability. Few N-pyridyl benzamide KCNQ2/Q3 potassium channel-opener subtypes were found to be effective in animal models of epilepsy (Amato et al., 2011). These channels modulate muscarine-mediated currents (IM current) that can in turn affect the firing rate of the neurons (Wang et al., 1998).  ICA subtypes are thought to be more selective and potent, and with less adverse effects than the KCNQ2-5 agonist retigabine (which is currently been discontinued), since they do not affect GABAergic synaptic transmission (Rogawski and Bazil, 2008). One of these drugs, ICA-105665, was shown to decrease photoparoxysmal EEG responses in patients with epilepsy (Kasteleijn-Nolst Trenite et al., 2013). 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid (ICA-110381) is a selective KCNQ2/Q3 potassium channel activator and was shown to reduce seizure severity in amygdala-kindled rats (Boehlen et al., 2013). We, therefore, sought to determine its effects in slices retrieved from drug-resistant temporal lobe epilepsy patients. Methods: After the determination of drug resistance and pre-surgical analysis for epileptic focus, 3 female and 3 male patients, 19 to 55 years old at the time of the surgery, underwent temporal lobe resection. Following the transport of resected tissue into the laboratory, 500 µm-thick coronal cortical slices were obtained. Extracellular field potentials were recorded from layer V of the temporal cortex after 4 hours of slice incubation. Seizure-like events (SLEs) were induced by combined application of 8 mM potassium and 50 µM bicuculline methodide. Fifty micromolar ICA-110381 was applied in bath solution when SLEs were stable. Results: In our small pilot study, 22 slices from six patients were investigated. ICA-110381 suppressed SLEs in 20 slices. Out of these 20 slices, complete block of SLEs and interictal activity was achieved in 7 slices (5 patients), while in 13 slices (6 patients), sporadic interictal spikes ( < 3 seconds) were prominent following suppresion of SLEs. In remaining 2 slices (2 patients), SLEs continued but their frequency was decreased 50% following drug application. Conclusions: ICA-110381 suppressed SLEs in 20 out of 22 temporal neocortex slices obtained from six patients with drug-resistant temporal lobe epilepsy. Our findings suggest that this drug may also be effective in certain patients with drug-resistant temporal lobe epilepsy. In combination with previous studies suggesting higher potency and possibly better safety, due to its more selective mechanism of action, ICA-110381 could be a good candidate for further therapy development for epilepsy. Funding: DFG grant He 1128/19-1, the GRK1123, and the EXC257 Neurocure,  EU FP7 integrated project DESIRE-(Grant agreement no: 602531)