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Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice.pdf (2.19 MB)

Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice

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posted on 2024-03-19, 09:45 authored by Omar MamadOmar Mamad, Mona HeilandMona Heiland, Andreas Ulrich Lindner, Thomas D M Hill, Ronan ConroyRonan Conroy, Kilian Rentrup, Amaya Sanz RodriguezAmaya Sanz Rodriguez, Elena Langa, Janosch P Heller, Oscar Moreno, Jordi Llop, Anindya Bhattacharya, James A Palmer, Marc Ceusters, Tobias EngelTobias Engel, David HenshallDavid Henshall

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 ex vivo radiotracer assay, we find that JNJ-54175446-treated mice at the end of recordings display a reduction in astrogliosis and altered microglia process morphology within the ipsilateral CA3 subfield of the hippocampus, but no difference in P2X7 receptor surface expression. The present study extends the characterisation of the drug-resistance profile of the intraamygdala kainic acid model in mice and provides further evidence that targeting the P2X7 receptor may have therapeutic applications in the treatment of temporal lobe epilepsy. 

Funding

Science Foundation Ireland (SFI) under Grant Number 16/RC/3948 and 21/RC/10294

European Regional Development Fund

Janssen Pharmaceutical Research and Development

Science Foundation Ireland under Grant Number 17/CDA/4708

European Union’s Horizon 2020 research and innovation programme under the Marie Sklowdowska-Curie grant agreement (No. 766124)

Irish Research Council (EpiGlymph) under grant IRCLA/2022/3828

Grant PID 2020-117656RB-I00 funded by the Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI) 10.13039/501100011033

Grant PRE 2019-089068 funded by MCIN/AEI

History

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Comments

The original article is available at https://www.frontiersin.org/

Published Citation

Mamad O, et al. Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice. Front Pharmacol. 2024;14:1308478.

Publication Date

8 January 2024

PubMed ID

38259288

Department/Unit

  • Physiology and Medical Physics
  • FutureNeuro Centre
  • School of Population Health
  • Data Science Centre

Publisher

Frontiers Media S.A

Version

  • Published Version (Version of Record)