AUTHOR=Mamad Omar , Heiland Mona , Lindner Andreas U. , Hill Thomas D. M. , Ronroy Ronan M. , Rentrup Kilian , Sanz-Rodriguez Amaya , Langa Elena , Heller Janosch P. , Moreno Oscar , Llop Jordi , Bhattacharya Anindya , Palmer James A. , Ceusters Marc , Engel Tobias , Henshall David C. TITLE=Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice JOURNAL=Frontiers in Pharmacology VOLUME=14 YEAR=2024 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1308478 DOI=10.3389/fphar.2023.1308478 ISSN=1663-9812 ABSTRACT=
There remains a need for new drug targets for treatment-resistant temporal lobe epilepsy. The ATP-gated P2X7 receptor coordinates neuroinflammatory responses to tissue injury. Previous studies in mice reported that the P2X7 receptor antagonist JNJ-47965567 suppressed spontaneous seizures in the intraamygdala kainic acid model of epilepsy and reduced attendant gliosis in the hippocampus. The drug-resistance profile of this model is not fully characterised, however, and newer P2X7 receptor antagonists with superior pharmacokinetic profiles have recently entered clinical trials. Using telemetry-based continuous EEG recordings in mice, we demonstrate that spontaneous recurrent seizures in the intraamygdala kainic acid model are refractory to the common anti-seizure medicine levetiracetam. In contrast, once-daily dosing of JNJ-54175446 (30 mg/kg, intraperitoneal) resulted in a significant reduction in spontaneous recurrent seizures which lasted several days after the end of drug administration. Using a combination of immunohistochemistry and