Qaddoumi Mohamed G, Ananthalakshmi Kethireddy V V, Phillips Oludotun A, Edafiogho Ivan O, Kombian Samuel B
Department of Pharmacology & Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat, Kuwait.
PLoS One. 2014 Jun 19;9(6):e99770. doi: 10.1371/journal.pone.0099770. eCollection 2014.
Epilepsy and other seizure disorders are not adequately managed with currently available drugs. We recently synthesized a series of dibromophenyl enaminones and demonstrated that AK6 and E249 were equipotent to previous analogs but more efficacious in suppressing neuronal excitation. Here we examined the actions of these lead compounds on in vitro and in vivo seizure models. In vitro seizures were induced in the hippocampal slice chemically (zero Mg2+ buffer and picrotoxin) and electrically using patterned high frequency stimulation (HFS) of afferents. In vivo seizures were induced in rats using the 6 Hz and the maximal electroshock models. AK6 (10 µM) and E249 (10 µM) depressed the amplitude of population spikes recorded in area CA1 of the hippocampus by -50.5±4.3% and -40.1±3.1% respectively, with partial recovery after washout. In the zero Mg2+ model, AK6 (10 µM) depressed multiple population spiking (mPS) by -59.3±6.9% and spontaneous bursts (SBs) by -65.9±7.2% and in the picrotoxin-model by -43.3±7.2% and -50.0±8.3%, respectively. Likewise, E249 (10 µM) depressed the zero-Mg2+-induced mPS by -48.8±9.5% and SBs by -55.8±15.5%, and in the picrotoxin model by -37.1±5.5% and -56.5±11.4%, respectively. They both suppressed post-HFS induced afterdischarges and SBs. AK6 and E249 dose-dependently protected rats in maximal electroshock and 6 Hz models of in vivo seizures after 30 min pretreatment. Their level of protection in both models was similar to that obtained with phenytoin Finally, while AK6 had no effect on locomotion in rats, phenytoin significantly decreased locomotion. AK6 and E249, suppressed in vitro and in vivo seizures to a similar extent. Their in vivo activities are comparable with but not superior to phenytoin. The most efficacious, AK6 produced no locomotor suppression while phenytoin did. Thus, AK6 and E249 may be excellent candidates for further investigation as potential agents for the treatment of epilepsy syndromes with possibly less CNS side effects.
目前可用的药物无法充分控制癫痫和其他发作性疾病。我们最近合成了一系列二溴苯基烯胺酮，并证明AK6和E249与之前的类似物具有同等效力，但在抑制神经元兴奋方面更有效。在此，我们研究了这些先导化合物在体外和体内癫痫模型中的作用。在海马切片中，通过化学方法（零镁离子缓冲液和印防己毒素）和使用传入神经的模式高频刺激（HFS）电诱导体外癫痫发作。在大鼠中使用6 Hz和最大电休克模型诱导体内癫痫发作。AK6（10 μM）和E249（10 μM）分别使海马CA1区记录的群体峰电位幅度降低了-50.5±4.3%和-40.1±3.1%，洗脱后有部分恢复。在零镁离子模型中，AK6（10 μM）使多重群体放电（mPS）降低了-59.3±6.9%，自发爆发（SBs）降低了-65.9±7.2%；在印防己毒素模型中，分别降低了-43.3±7.2%和-50.0±8.3%。同样，E249（10 μM）使零镁离子诱导的mPS降低了-48.8±9.5%，SBs降低了-55.8±15.5%；在印防己毒素模型中，分别降低了-37.1±5.5%和-56.5±11.4%。它们都抑制了HFS后诱导的放电和SBs。在30分钟预处理后，AK6和E249在最大电休克和6 Hz体内癫痫模型中剂量依赖性地保护大鼠。它们在两种模型中的保护水平与苯妥英钠相似。最后，虽然AK6对大鼠运动没有影响，但苯妥英钠显著降低了运动。AK6和E249在体外和体内对癫痫发作的抑制程度相似。它们的体内活性与苯妥英钠相当但不优于苯妥英钠。最有效的AK6没有产生运动抑制，而苯妥英钠则有。因此，AK6和E249可能是作为治疗癫痫综合征的潜在药物进行进一步研究的优秀候选药物，可能具有较少的中枢神经系统副作用。
