Abstracts

Rationale: The onset of most epileptic conditions is based on various brain etiologies, such as developmental abnormalities, inflammations, or tumors. Basic epilepsy research usually requires some animal models. However, the probability that these models reflect the etiological aspect remains unresolved. To overcome the issue of animal models, ex vivo functional analysis of human epileptic foci is a good option. Using surgically resected human epileptic foci, here we investigated pharmacological effects of E2730, which is a novel selective uncompetitive GAT-1 inhibitor discovered as a new candidate antiseizure medication (ASM), on epileptiform activities.

Methods: First, the focal tissues of people with epilepsy were transported alive to the laboratory immediately after surgical resection. Further, coronal sequential brain slices were prepared and incubated in an oxygenated artificial cerebrospinal fluid at 30°C. Acute brain slices were left active for more than 8 hours under these circumstances. Moreover, we performed optical imaging or field potential recordings to detect epileptiform activities ex vivo, after which the pharmacological effect of E2730 on epileptiform activity was evaluated through bath application. Antiepileptic effects were finally compared with those of Carbamazepine (CBZ) as a control.

Results: Investigations were conducted in seven focal epilepsy cases. These included four with focal cortical dysplasia type II and three hippocampal sclerosis patients with mesial temporal lobe epilepsy. Spontaneous epileptiform activity was detected in all cases. Results also showed that, although both E2730 and CBZ dose-dependently attenuated the frequency of these spontaneous epileptiform events, their effect differed in detail. Specifically, while CBZ attenuated the amplitude of spontaneous epileptiform activities without decreasing event frequency, the frequency of spontaneous epileptiform events was primarily decreased in E2730. Furthermore, E2730 inhibited the transmission of abnormal neural circuits. Besides, recurrent activities induced by mossy fiber stimulation were observed in the dentate gyrus of hippocampal sclerosis cases, suggesting the presence of abnormal neural circuits known as mossy fiber sprouting. Nevertheless, E2730 specifically suppressed these recurrent activities without affecting normal neuronal excitability.

Conclusions: These results indicate that E2730 has novel antiepileptic effects for managing human epileptic foci than conventional ASMs.

Funding: Eisai Co., Ltd