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

 描述（由申请人提供）：热性惊厥影响高达5%的5岁以下儿童，是该年龄组儿童中最常见的癫痫发作。目前对热性惊厥的治疗是有限的和不充分的，经常导致长期不受控制的惊厥。临床 观察结果表明，早期生命延长的热性惊厥和慢性颞叶癫痫的后期发展之间可能存在病因学联系。尽管有热性惊厥的儿童癫痫风险增加，但这些惊厥即使是复发性的，也通常不用抗惊厥药治疗。在过去，苯巴比妥已被用于预防复发性热性惊厥的治疗超过25年，但抗惊厥预防不再推荐，因为副作用似乎超过了潜在的好处。设计有效治疗的主要障碍之一是，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。这一建议是基于我们的观察，温度依赖性增加的内在神经元兴奋性驱动的L-型电压门控钙通道起着至关重要的作用，在产生热性惊厥在幼稚啮齿动物。我们将使用膜片钳记录和单细胞RT-PCR从急性切片来表征所涉及的通道的精确分子身份，并测试假设相同的通道也是从Scn 1atm 1 Kea小鼠（Dravet综合征的动物模型）获得的神经元中的热去极化的关键介质。进一步的实验将测试尼莫地平可以防止从Dravet综合征小鼠获得的切片中癫痫发作的发展的假设。我们将观察尼莫地平浴后对温度阈值、癫痫放电频率和幅度的影响。最后，我们将使用行为分析和EEG记录来测试尼莫地平治疗Dravet综合征啮齿动物模型中癫痫发作的功效。如果成功，这些实验可能具有直接的翻译相关性，因为二氢吡啶类药物已在临床上用于治疗高血压数十年，不良反应可忽略不计。因此，尼莫地平的使用很可能 治疗或预防热性惊厥将没有负面副作用，并且该化合物可用于治疗所有类型的热性惊厥，包括迫切需要新的药理学治疗的Dravet患者中的热性惊厥。

 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.