瑞马唑仑抑制匹罗卡品诱导的小鼠惊厥性癫痫持续状态的发生

The efficacy of Remimazolam Suppresses Piloqueine-induced convulsive status epilepticus in mice

关键词:  惊厥性癫痫持续状态  瑞马唑仑  匹罗卡品  脑电图  地西泮

Key words:  convulsive status epilepticus  remimazolam  pilocarpine  electroencephalogram  diazepam

摘要:

目的研究不同剂量瑞马唑仑单次腹腔注射对匹罗卡品诱导小鼠惊厥性癫痫持续状态（convulsive status epilepticus, CSE）模型中的作用效果。 方法将59只雄性C57BL/6J小鼠随机分成以下6组： 模型对照组、3 mg/kg地西泮组、10 mg/kg地西泮组、3 mg/kg瑞马唑仑组、10 mg/kg瑞马唑仑组、40 mg/kg瑞马唑仑组。各组均给予1 mg/kg阿托品腹腔注射以减轻匹罗卡品的外周胆碱能副作用，等待20 min后，将匹罗卡品按照340 mg/kg的剂量予每只以诱导CSE模型，对照组则根据小鼠体质量腹腔注射相同剂量的生理盐水，实验组进行各组药物腹腔注射，根据Racine量表进行行为学分级并记录30 min内各组小鼠癫痫发作状况，同时埋置颅骨电极，记录并分析CSE模型小鼠的脑电变化。4~5周后视频监测慢性期自发性癫痫发作。 结果340 mg/kg匹罗卡品小鼠的Racine评分4级及以上死亡率为53%；所有剂量瑞马唑仑均能有效终止急性CSE发作；药物早期干预减少了CSE模型中慢性自发性癫痫的发作率；在体脑电结果显示，癫痫发作时δ和γ波占优势。药物干预后，β和γ波增加。 结论表明瑞马唑仑在临床前模型中具有快速干预CSE的潜力。这一发现为进一步的临床研究奠定了基础，强调了该药物作为现有苯二氮类药物治疗更安全、更有效替代品的前景。

Abstract:

ObjectiveTo explore the efficacy of single-dose intraperitoneal injection of different doses of remimazolam on pilocarpine-induced convulsive status epilepticus(CSE) model in mice, providing guidance for clinical medication. MethodsFifty-nine male C57BL/6J mice were randomly divided into the following 6 groups： model control group, diazepam groups of 3 mg/kg and 10 mg/kg, and remimazolam groups of 3 mg/kg, 10 mg/kg and 40 mg/kg. Each group was given intraperitoneal injection of 1 mg/kg atropine to alleviate the peripheral cholinergic effects of pilocarpine. After a 20-minute wait, pilocarpine was administered to induce the CSE model at a dose of 340 mg/kg for each epileptic group, while the control group were given intraperitoneal injection of the same dose of saline according to the mouses weight. The experimental groups received intraperitoneal injection of different drugs for each group. The seizures of mice in each group within 30 minutes were recorded according to Racines classification. At the same time, the skull electrodes were implanted, and the changes of brain electrical rhythm in vivo were recorded and analyzed by CSE modeling. After 4-5 weeks video monitoring of spontaneous recurrent seizures(SRS). ResultsThe mortality rate of mice receiving 340 mg/kg pilocarpine with Racine score of Ⅳ and above was 53%. All doses of remimazolam could effectively terminate CSE. Early drug intervention reduced the onset of chronic spontaneous epilepsy. In the results of electroencephalogram(EEG), δ and γ rhythms predominated during seizures. After drug interventions, the β and γ rhythms increased. ConclusionRemimazolam shows potential for rapid intervention in CSE in preclinical models. This finding lays the foundation for further clinical research, emphasizing the prospect of this drug as a safer and more effective alternative to existing benzodiazepine drugs.