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会对神经系统功能产生不利影响。 这对神经系统疾病的治疗提出了挑战，在神经系统疾病中，潜在的疾病和 治疗两者都可能有副作用。这方面的一个例子是平衡药物的选择， 癫痫是婴儿期最常见的神经系统疾病之一。新生儿癫痫发作是一种 缺氧（或缺氧-缺血）后常见;这些癫痫发作通常采用 抗惊厥药缺氧诱导的癫痫发作与生命后期风险的显著增加相关 癫痫发作，以及严重的发育迟缓和智力残疾。然而，由于 与癫痫发作和药物治疗的结果之间存在混淆。在本申请中，我们建议 评估：（1）缺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），（3）神经保护干预的有效性 （褪黑激素）。我们将确定癫痫发作和药物对大脑发育的影响程度， 生物化学（程序性细胞死亡，氧化应激的评估），神经生理学（膜片钳 海马CA 1区神经元的记录）和行为（成年人学习和记忆测试 在婴儿时期接触药物和/或癫痫发作的动物）。我们还将评估药物安全性的生物标志物， 氧化应激的外周测量和动物的高分辨率磁共振成像 遭受这些早期生活的侮辱最后，我们将确定我们的神经保护干预是否改善了 与癫痫发作和/或药物治疗相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.