Amhaoul Halima, Ali Idrish, Mola Marco, Van Eetveldt Annemie, Szewczyk Krystyna, Missault Stephan, Bielen Kenny, Kumar-Singh Samir, Rech Jason, Lord Brian, Ceusters Marc, Bhattacharya Anindya, Dedeurwaerdere Stefanie
Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
Neuropharmacology. 2016 Jun;105:175-185. doi: 10.1016/j.neuropharm.2016.01.018. Epub 2016 Jan 15.
The available pharmacotherapy for patients with epilepsy primarily address the symptoms and are ineffective in about 40% of patients. Brain inflammation gained support as potential target for developing new therapies, especially the P2X7 receptor (P2X7R), involved in processing of IL-1β, might be an interesting candidate. This study was designed to investigate the effect of a novel P2X7R antagonist on the severity and on the number of chronic spontaneous recurrent seizures (SRS), which was unexplored until now.
After one-week of vehicle treatment (20% HP-β-cyclodextrin), JNJ-42253432 was administered subcutaneously for another week under continuous video-electroencephalography monitoring (n = 17) in Sprague Dawley rats 3 months after kainic acid-induced status epilepticus. The proportion of different seizure classes, as well as the number of SRS/day were calculated for the vehicle and treatment period. In addition, post-mortem microglial activation and astrogliosis were assessed.
A significant decrease of the proportion of type 4-5 SRS (p < 0.05), while an increase of type 1-3 was demonstrated (p < 0.05) from the vehicle to the treatment period. There was no effect of the P2X7R antagonist on the number of SRS/day or the glial markers.
The P2X7R antagonist gave rise to a less severe profile of the chronic seizure burden without suppressing the SRS frequency. More studies are needed to unravel the underlying mechanisms of the beneficial effect on seizure severity and whether the administration of the compound during early epileptogenesis could induce long-term disease-modifying effects.
癫痫患者现有的药物治疗主要针对症状，约40%的患者治疗无效。脑炎症作为开发新疗法的潜在靶点得到了支持，特别是参与白细胞介素-1β加工的P2X7受体（P2X7R）可能是一个有价值的候选靶点。本研究旨在探讨一种新型P2X7R拮抗剂对慢性自发性复发性癫痫发作（SRS）严重程度和发作次数的影响，这在之前尚未被研究过。
在用海藻酸诱导癫痫持续状态3个月后的Sprague Dawley大鼠中，在连续视频脑电图监测下（n = 17），先给予1周的赋形剂（20% HP-β-环糊精）治疗，然后皮下注射JNJ-42253432再持续1周。计算赋形剂治疗期和药物治疗期不同癫痫发作类型的比例以及每日SRS发作次数。此外，还评估了死后小胶质细胞激活和星形胶质细胞增生情况。
从赋形剂治疗期到药物治疗期，4-5型SRS的比例显著降低（p < 0.05），而1-3型SRS的比例增加（p < 0.05）。P2X7R拮抗剂对每日SRS发作次数或胶质细胞标志物没有影响。
P2X7R拮抗剂减轻了慢性癫痫发作负担的严重程度，但未抑制SRS频率。需要更多研究来阐明其对癫痫发作严重程度产生有益作用的潜在机制，以及在癫痫发生早期给予该化合物是否能诱导长期的疾病改善作用。
