目的:癫痫突然意外死亡(SUDEP)是一种被低估的癫痫并发症。先前的研究表明,在诱发性癫痫发作模型中,5-羟色胺能神经传递的增强抑制了癫痫发作引起的猝死。然而,目前尚不清楚5-羟色胺(5-HT)功能升高是否会阻止自发性癫痫引起的死亡(SSIM),这是人类SUDEP的特征。我们研究了通过三种不同药理机制对Dravet小鼠SSIM起作用的5-HT增强剂的作用,表现出很高的SUDEP发生率,模拟人类Dravet综合征。
方法:评估了两种性别的Dravet小鼠的自发性癫痫发作特征和增强5-HT介导的神经传递的药物诱导的SSIM发生率的变化。氟西汀(选择性5-HT再摄取抑制剂),芬氟拉明(5-HT释放剂和激动剂),SR57227(一种特定的5-HT3受体激动剂),或盐水(媒介物)在8天的时间内对Dravet小鼠进行腹膜内给药,并检查了这些治疗对SSIM的影响。
结果:Dravet小鼠的自发性癫痫发作通常从野外奔跑发展到有或没有SSIM的强直性癫痫发作。氟西汀30mg/kg,但不是20或5毫克/千克,与车辆控制相比,SSIM显著降低。芬氟拉明1-10毫克/千克,但不是0.2mg/kg,完全保护Dravet鼠标免受SSIM的侵害,所有老鼠都存活下来。与车辆控制相比,SR57227在20mg/kg,但不是10或5毫克/千克,显著降低SSIM。这些药物对SSIM的影响与性别无关。
结论:我们的数据表明,氟西汀可提高5-羟色胺能功能,芬氟拉明,或SR57227以与性别无关的方式显着减少或消除Dravet小鼠中的SSIM。这些发现表明,5-羟色胺能神经传递缺陷可能在SSIM的发病机制中起重要作用。还有氟西汀和芬氟拉明,这是美国食品和药物管理局批准的药物,可能潜在地预防高危患者的SUDEP。
OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome.
METHODS: Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined.
RESULTS: Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex.
CONCLUSIONS: Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.