A cholecystokinin 2 receptor antagonist alleviates seizure severity in a mouse and miniature pig model of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common type of acquired epilepsy characterized by recurrent spontaneous seizures. The entorhinal cortex (EC) lies in the medial temporal lobe and serves as a relay center between the hippocampus and neocortex, and contains cholecystokinin-positive (CCK+) neurons. Increased CCK expression has been reported in patients with TLE suggesting its role in epilepsy development. Here, we sought to understand whether CCK+ neurons in EC are involved in TLE development and also to evaluate the therapeutic efficacy of a CCK-2 receptor antagonist in ameliorating seizure severity in a mouse and miniature pig model of TLE. Experiments were carried out using male C57BL/6J mice, male and female miniature Bama pigs. Intrahippocampal kainic acid (KA) model of TLE was adopted to assess the dynamics of CCK-positive neurons in EC coupled with fibre photometry recording of calcium dynamics. CCK-2 receptor antagonist was administered intraperitoneally and intramuscularly in mice and miniature pigs, respectively, to evaluate its therapeutic effect on seizure frequency. The calcium dynamics of CCK-positive neurons in the EC of TLE mice were increased during both inter-ictal phase and spontaneous seizures, signifying enhanced neuronal excitability of CCK-positive neurons. Administration of CCK-2 receptor antagonist YF476 significantly suppressed convulsive seizure frequency during and post-treatment in TLE mice and was also effective in alleviating the frequency of severe and mild seizures in TLE miniature pigs when compared with phenytoin and carbamazepine. This study reveals a novel strategy for treating TLE and it provides the possibility of YF476 being adopted as a new anti-seizure drug. © 2025 The Author(s).