Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.
Department of Neuroscience, School of Translational Medicine,, Monash University, Melbourne, Victoria, Australia.
Epilepsia Open. 2024 Oct;9(5):1826-1836. doi: 10.1002/epi4.13016. Epub 2024 Aug 3.
We evaluated huperzine A treatment in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model of genetic generalized epilepsy (GGE) with absence seizures.
Adult male GAERS (N = 15) were implanted with EEG recording electrodes 10 days before receiving study drug. Each animal received the following six treatments as a single, intraperitoneal dose, 7 days apart (in random order): huperzine A (0.3, 1.0, or 3.0 mg/kg), two periods of vehicle (0.9% NaCl), or ethosuximide (100 mg/kg) as a positive control. Electroencephalograms (EEGs) were acquired for 24 h before and after each treatment and analyzed for seizure activity during the 90-min period immediately post-treatment, including 30-min intervals at 30, 60, and 90 min. Additional analyses evaluated seizure activity over the 24-h post-treatment period using 60-min intervals at 6, 12, and 24 h. The cumulative 24-h periods before and after each administered treatment were also compared.
Two-way ANOVA showed a treatment difference [F = 3.592, p < 0.0001] on the number of seizures over the first 90-min post-treatment (primary outcome); Tukey's post hoc analyses showed that, compared to vehicle, huperzine A (3.0 mg/kg) significantly reduced seizures in the 30-min (p = 0.02) and 60-min (p = 0.001) intervals, and ethosuximide significantly reduced seizures at all measured time intervals except the 1-h blocks at 12 and 24 h. Huperzine A 3.0 mg/kg and ethosuximide significantly reduced seizures during the cumulative 24-h post-treatment period relative to pretreatment baseline. While huperzine A 3.0 mg/kg did not differ significantly from ethosuximide at any time point, the study was not designed to evaluate non-inferiority. The only adverse event after huperzine A or ethosuximide was mild, dose-dependent sedation.
Huperzine A potently suppressed absence-like seizures in GAERS, albeit with a shorter duration of action relative to ethosuximide, showing promise for clinical efficacy in GGE.
This study looked at how huperzine A affects seizures in rats with similar abnormal brain activity as seen in humans with absence epilepsy. Rats received different treatments, placebo (i.e., saline solution), huperzine A, and ethosuximide. Ethosuximide is considered a gold standard treatment for absence epilepsy. We recorded brain activity to measure seizures before and after each treatment. We found that huperzine A (3.0 mg/kg) reduced seizures soon after treatment, like ethosuximide. Both treatments appeared safe, causing only mild sleepiness. The study shows that huperzine A could be a good new treatment for a type of absence epilepsy.
我们评估了石杉碱甲在具有失神发作的斯特拉斯堡遗传性全面性癫痫大鼠（GAERS）模型中的治疗作用，这是一种遗传性全面性癫痫（GGE）。
成年雄性 GAERS（N=15）在接受研究药物前 10 天植入脑电图记录电极。每只动物接受以下六种治疗中的一种，作为单次腹腔内给药，间隔 7 天（随机顺序）：石杉碱甲（0.3、1.0 或 3.0mg/kg）、两个时期的载体（0.9%生理盐水）或乙琥胺（100mg/kg）作为阳性对照。在每次治疗前后 24 小时内采集脑电图（EEG）并进行分析，以评估治疗后 90 分钟内的癫痫发作活动，包括 30 分钟间隔时间在 30、60 和 90 分钟。额外的分析使用 60 分钟间隔时间在 6、12 和 24 小时评估治疗后 24 小时期间的癫痫发作活动。还比较了每个给药治疗前后的累积 24 小时期。
双向方差分析显示，在治疗后最初 90 分钟内（主要结果）的癫痫发作次数存在治疗差异[F=3.592，p<0.0001]；Tukey 的事后分析显示，与载体相比，石杉碱甲（3.0mg/kg）在 30 分钟（p=0.02）和 60 分钟（p=0.001）间隔内显著减少了癫痫发作，乙琥胺在所有测量的时间间隔内均显著减少了癫痫发作，除了在 12 和 24 小时的 1 小时块内。石杉碱甲 3.0mg/kg 和乙琥胺在与治疗前基线相比的累积治疗后 24 小时期间显著减少了癫痫发作。虽然石杉碱甲 3.0mg/kg在任何时间点与乙琥胺均无显著差异，但该研究并非旨在评估非劣效性。石杉碱甲或乙琥胺治疗后唯一的不良事件是轻度、剂量依赖性镇静。
石杉碱甲在 GAERS 中有力地抑制了失神样癫痫发作，尽管其作用持续时间短于乙琥胺，但在 GGE 的临床疗效方面显示出了希望。
