Sawicka Katarzyna M, Wawryniuk Agnieszka, Zwolak Agnieszka, Daniluk Jadwiga, Szpringer Monika, Florek-Luszczki Magdalena, Drop Bartlomiej, Zolkowska Dorota, Luszczki Jarogniew J
Medical University in Lublin, Lublin, Poland.
The Jan Kochanowski University in Kielce, Kielce, Poland.
Neurochem Res. 2017 Apr;42(4):1038-1043. doi: 10.1007/s11064-016-2136-1. Epub 2017 Jan 12.
Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.
尽管超极化激活的环核苷酸门控（HCN）通道在神经元兴奋性和突触传递中的作用仍不明确，但据推测HCN通道可能参与癫痫发作活动。本研究的目的是评估伊伐布雷定（一种HCN通道抑制剂）对四种经典抗癫痫药物（卡马西平、苯巴比妥、苯妥英和丙戊酸盐）对小鼠最大电休克诱导癫痫发作的保护作用的影响。通过经耳电极施加电流（正弦波，25 mA，刺激持续时间0.2 s）在成年雄性白化瑞士小鼠中诱发强直性癫痫发作（最大惊厥）。在小鼠中测量伊伐布雷定与经典抗癫痫药物组合的急性不良反应概况以及全脑抗癫痫药物浓度。结果表明，在小鼠最大电休克诱导癫痫发作模型中，伊伐布雷定（10 mg/kg，腹腔注射）显著增强了丙戊酸盐的抗惊厥活性，并显著降低了苯妥英的抗惊厥活性。在小鼠最大电休克诱导癫痫发作试验中，伊伐布雷定（10 mg/kg）对卡马西平和苯巴比妥的抗惊厥效力没有影响。伊伐布雷定（10 mg/kg）显著降低了小鼠全脑苯妥英浓度，对小鼠全脑丙戊酸盐浓度没有影响。总之，在小鼠最大电休克诱导癫痫发作模型中，伊伐布雷定增强丙戊酸盐的抗惊厥作用本质上是药效学的。由于药代动力学相互作用以及小鼠中苯妥英抗惊厥作用的降低，伊伐布雷定与苯妥英联合使用时需要特别注意。从临床前观点来看，伊伐布雷定与卡马西平和苯巴比妥的组合是中性的。
