Structural and functional sequelae of neonatal anticonvulsant exposure: drug-seizure interactions

项目摘要 在大脑发育的关键时期进行药物治疗可能会对神经系统功能产生不利影响。 这对神经疾病的治疗提出了挑战，在这种情况下，基础疾病和 这两种治疗方法都可能产生不良影响。这方面的一个例子是平衡患者的药物选择 癫痫的治疗，这是婴儿期最常见的神经疾病之一。新生儿癫痫发作是一种 常发生在缺氧(或缺氧-缺血)后；这些癫痫发作通常用积极的 抗惊厥药。低氧诱导的癫痫发作与晚年风险的显著增加有关 癫痫，以及严重的发育迟缓和智力残疾。然而，应有的结果是 对于癫痫的发作和药物治疗的结果是混乱的。在本申请中，我们建议 评估：(1)低氧诱导癫痫发作的效果；(2)三种最常见的抗癫痫药物的效果 用于婴儿(苯巴比妥、苯妥英、左乙拉西坦)，以及(3)神经保护性干预的疗效 (褪黑激素)。我们将在这个水平上确定癫痫发作和药物对大脑发育的影响程度 生物化学(细胞程序性死亡、氧化应激的评估)、神经生理学(膜片钳 来自海马区CA1区神经元的记录)和行为(成人学习和记忆测试 婴儿时期接触药物和/或癫痫的动物)。我们还将通过以下方式评估药物安全性的生物标记物 动物氧化应激的外周测量和高分辨率磁共振成像 暴露在这些早年生活的侮辱中。最后，我们将确定我们的神经保护干预是否改善 与癫痫发作和/或药物治疗有关的部分或全部不良后果。

Project Summary Pharmacotherapy during critical periods of brain development can adversely affect nervous system function. This poses a challenge for the treatment of neurological disorders, where the underlying illness and the treatment both may have adverse effects. One example of this is balancing the choice of medication for the treatment of seizures, one of the most common neurological disorders of infancy. Seizures in neonates are a common occurrence after hypoxia (or hypoxia-ischemia); these seizures are typically aggressively treated with anticonvulsant drugs. Hypoxia-induced seizures are associated with a profound increase in risk for later-in-life seizures, as well as significant developmental delays and intellectual disabilities. However, the outcomes due to the seizures and the outcomes due to the drug therapy are confounded. In this application, we propose to evaluate: (1) the effect of hypoxia-induced seizures, (2) the effect of the three most common anti-seizure drugs used in babies (phenobarbital, phenytoin, levetiracetam), and (3) the efficacy of a neuroprotective intervention (melatonin). We will determine the degree to which seizures and drugs influence brain development at the level of biochemistry (assessment of programmed cell death, oxidative stress), neurophysiology (patch-clamp recordings from neurons in hippocampal CA1 subfield), and behavior (tests of learning and memory in adult animals exposed to drugs and/or seizures as babies). We will also evaluate biomarkers of drug safety through peripheral measurement of oxidative stress and high-resolution magnetic resonance imaging of animals exposed to these early life insults. Finally, we will determine if our neuroprotective intervention ameliorates some, or all, of the adverse outcomes associated with seizures and/or drug treatment.