L-type channels as pharmacological targets for the treatment and prevention of febrile seizures

 描述(申请人提供)：热性惊厥影响多达5%的5岁以下儿童，是这一年龄段儿童中最常见的惊厥。目前对热性惊厥的治疗是有限和不充分的，常常导致长期失控的惊厥。临床 观察表明，早期生命延长的发热性癫痫与慢性颞叶癫痫的晚期发展之间可能存在病因学联系。尽管患有热性癫痫的儿童癫痫风险增加，但即使是反复发作，这些癫痫发作通常也不会得到抗惊厥药物的治疗。在过去，苯巴比妥被用于预防反复发热性癫痫发作超过25年，但现在不再推荐使用抗惊厥预防药物，因为副作用似乎超过了潜在的益处。设计有效的治疗方法的主要障碍之一是，尽管它们与体温过高有明显的联系，但热性惊厥的详细分子机制仍不清楚。我们观察到，L类电压门控性钙通道引起的神经元兴奋性的温度依赖性升高在幼年啮齿动物高热惊厥的发生中起着关键作用。我们将使用膜片钳记录和来自急性切片的单细胞RT-PCR来表征所涉及的通道的精确分子身份，并测试从Drave综合征的动物模型Scn1atm1Kea小鼠获得的神经元中相同通道也是高温去极化的关键介质的假设。进一步的实验将验证尼莫地平可以防止德拉韦综合征小鼠脑片癫痫发作的假设。我们将研究应用尼莫地平浴对癫痫放电的温度阈值、频率和幅度的影响。最后，我们将使用行为学分析和脑电记录来验证尼莫地平对Dravet综合征啮齿动物模型癫痫发作的治疗效果。如果成功，这些实验可能会立即产生翻译上的相关性，因为二氢吡啶几十年来一直在临床上用于治疗高血压，副作用可以忽略不计。因此，尼莫地平很可能用于治疗 治疗或预防热性惊厥不会有任何副作用，这种化合物可用于治疗所有类型的热性惊厥，包括急需新的药物治疗的Drave型癫痫患者。

 DESCRIPTION (provided by applicant): Febrile seizures affect up to 5% of children under the age of 5, and are the most common seizures in children of this age group. Current treatment of febrile seizures is limited and inadequate, often resulting in long uncontrolled seizures. Clinical observations suggest a possible etiologic link between early life prolonged febrile seizures and later development of chronic temporal lobe epilepsy. Despite increased risk of epilepsy in children with febrile seizures, these seizures are routinely not treated with anticonvulsants even if they are recurrent. In the past, phenobarbital had been used for over 25 years as prophylaxis in the treatment of recurrent febrile seizures, but anticonvulsant prophylaxis is no longer recommended because side effects appeared to outweigh the potential benefits. One of the main hurdles to the design of effective treatments is that, despite their obvious association with hyperthermia, the detailed molecular mechanisms of febrile seizures remain unclear. This proposal is based on our observation that a temperature dependent increase in intrinsic neuronal excitability driven by L-type voltage-gated calcium channels plays a critical role in the generation of febrile seizures in naive rodents. We will use patch clamp recordings and single-cell RT-PCR from acute slices to characterize the precise molecular identity of the channels involved and test the hypothesis that the same channels are also critical mediators of hyperthermic depolarization in neurons obtained from Scn1atm1Kea mice, an animal model of Dravet syndrome. Further experiments will test the hypothesis that nimodipine can prevent the development of seizures in slices obtained from the Dravet syndrome mice. We will investigate the effect of bath applied nimodipine on the temperature threshold, frequency and magnitude of the epileptic discharges. Finally, we will use behavioral analysis and EEG recordings to test the efficacy of nimodipine for the treatment of seizures in the rodent model of Dravet syndrome. If successful, these experiments may have immediate translational relevance because dihydropyridines have been used for decades in clinical context for the treatment of high blood pressure with negligible adverse effects. Therefore it is likely that the use of nimodipine for the treatment or prevention of febrile seizures would be devoid of negative side effects and that this compound could be used for the treatment of all types of febrile seizures, including those in Dravet patients for which novel pharmacological treatments are badly needed.