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
Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
FutureNeuro SFI Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Front Pharmacol. 2024 Jan 8;14:1308478. doi: 10.3389/fphar.2023.1308478. eCollection 2023.
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 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.
对于难治性颞叶癫痫，仍需要新的药物靶点。ATP门控的P2X7受体协调对组织损伤的神经炎症反应。先前对小鼠的研究报告称，P2X7受体拮抗剂JNJ - 47965567在癫痫的杏仁核内注射 kainic 酸模型中可抑制自发性癫痫发作，并减少海马体中的伴随胶质增生。然而，该模型的耐药性特征尚未完全明确，且具有更优药代动力学特征的新型P2X7受体拮抗剂最近已进入临床试验。通过对小鼠进行基于遥测的连续脑电图记录，我们证明杏仁核内注射 kainic 酸模型中的自发性复发性癫痫发作对常用抗癫痫药物左乙拉西坦具有耐药性。相比之下，每日一次给予JNJ - 54175446（30 mg/kg，腹腔注射）可显著减少自发性复发性癫痫发作，且在药物给药结束后这种减少持续了数天。通过免疫组织化学和放射性示踪剂检测相结合的方法，我们发现记录结束时接受JNJ - 54175446治疗的小鼠海马体同侧CA3亚区内星形胶质细胞增生减少，小胶质细胞突起形态改变，但P2X7受体表面表达无差异。本研究扩展了对小鼠杏仁核内注射 kainic 酸模型耐药性特征的描述，并提供了进一步的证据表明靶向P2X7受体可能在颞叶癫痫治疗中具有治疗应用价值。
