Sex differences in SUDEP susceptibility: the role of progesterone and estradiol

项目摘要： 癫痫是全世界最常见的神经系统疾病之一。尽管有大量的 在现有的抗癫痫药物中，超过三分之一的癫痫患者无法 用药物控制他们的癫痫发作，使他们在年内猝死的风险更高 癫痫(SUDEP)。SUDEP是耐药癫痫患者死亡的主要原因， 虽然它分布在所有年龄段，并影响男性和女性，但在 男性。在一些患有癫痫的女性中，癫痫发作的频率和严重程度是已知的fl， 与性激素水平的变化相对应。可能，性类固醇在调节 癫痫发作，可能是SUDEP发病率性别差异的原因。 为了评估性类固醇在癫痫发作和SUDEP易感性中的作用，我们使用了急性和慢性 黄体酮和雌二醇(P+E)对Drave型综合征(DS)小鼠模型的治疗作用 Scn1aR1407X/+功能缺失突变。我们的初步数据表明，SUDEP的发病率 P+E缺陷急性处理的雌性和雄性小鼠的癫痫表型均有所改善 在5-羟色胺(5-羟色胺)系统和Defi中，GABA能功能与癫痫和 苏德普。动物研究表明，P+E的急性和慢性治疗可增加5-羟色胺 在大脑中的浓度，并增加紧张性GABA在海马区的抑制。更进一步，性 众所周知，类固醇可以刺激呼吸，潜在地提供了一种拯救呼吸的方法 在DS小鼠中观察到表型。因此，我们将检验以下工作假设：1)P+E降低 通过减少发作频率和/或严重程度以及刺激呼吸来减少SUDEP的发生率，以及2) P+E的抗惊厥作用是由5-羟色胺和/或GABA介导的。慢性和慢性精神分裂症的影响 将通过视频评估急性P+E治疗对癫痫发作、SUDEP发生率和呼吸的影响。 EEG/EKG监测自发性和热性惊厥。使用DS小鼠，其中5- 羟色胺神经元已被基因删除，我将确定5-羟色胺是否介导 急性和慢性P+E治疗的抗惊厥作用。最后，我将评估 DS小鼠海马片GABA-A介导的紧张性抑制与野生型的差异 使用全细胞膜片钳的急性应用和不急性应用P+E或其代谢物的类型 录音。这项拟议的工作将为性激素在SUDEP中的作用提供更清晰的见解 发病率。此外，由于癫痫发作易感性的性别差异在癫痫中是一个普遍关注的问题， 确认性类固醇如何影响5-羟色胺能和GABA能神经通路，可以提供 临床医生为男性和女性癫痫患者提供更有效的治疗策略。

Project Abstract: Epilepsy is one of the most common neurological diseases worldwide. Despite a large number of available antiepileptic drugs (AEDs), more than one-third of people with epilepsy are not able to control their seizures with medication, putting them at higher risk for sudden unexpected death in epilepsy (SUDEP). SUDEP is a major cause of death in patients with drug-resistant epilepsy, and while it is distributed across all ages and affects both males and females, it is more prevalent in males. In some epileptic females, seizure frequency and severity are known to fluctuate, corresponding to changes in sex steroid levels. Possibly, sex steroids play a role in the regulation of seizures and might account for the sex difference in SUDEP incidence. To evaluate the role of sex steroids in seizure and SUDEP susceptibility, we used acute and chronic treatment of progesterone and estradiol (P+E) in a mouse model of Dravet Syndrome (DS) with a Scn1aR1407X/+ loss-of-function mutation. Our preliminary data demonstrate that SUDEP incidence and the seizure phenotype are improved in female and male mice acutely treated with P+E. Defects in the serotonin (5-HT) system and deficits in GABAergic function are associated with seizures and SUDEP. Animal studies have shown that acute and chronic treatment with P+E can increase 5-HT concentration in the brain and increase tonic GABA inhibition in the hippocampus. Further, sex steroids are known to stimulate breathing, potentially providing a method to rescue the respiratory phenotype observed in DS mice. Thus, we will test the working hypotheses that 1) P+E decrease SUDEP incidence by reducing seizure frequency and/or severity, and stimulating breathing, and 2) the anticonvulsant effects of P+E are mediated by serotonin and/or GABA. The effect of chronic and acute P+E treatment on seizures, SUDEP incidence, and breathing will be assessed through video- EEG/EKG monitoring of spontaneous and hyperthermia-induced seizures. Using DS mice in which 5- HT neurons have been genetically deleted, I will determine whether serotonin mediates the anticonvulsant effects conferred by acute and chronic P+E treatment. Lastly, I will assess for differences in GABA-A mediated tonic inhibition in the hippocampal slice of DS mice compared to wild type with and without acute application of P+E, or their metabolites, using whole-cell patch-clamp recordings. The proposed work will provide clearer insight into the role of sex steroids in SUDEP incidence. Further, as sex differences in seizure susceptibility are a widespread concern in epilepsy, identifying how sex steroids impact the serotonergic and GABAergic neural pathways, could provide clinicians with more effective treatment strategies for both male and female epilepsy patients.