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

新生儿抗惊厥药物暴露的结构和功能后遗症：药物与癫痫发作的相互作用

基本信息

批准号：
10454335
负责人：
Patrick Alexander Forcelli
金额：
$ 47.01万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454335
关键词：
Acute Adult Adverse effects Affect Anticonvulsants Antiepileptic Agents Antioxidants Apoptosis Apoptotic Behavioral Biochemistry Biological Markers Brain Brain Hypoxia-Ischemia Carbamazepine Cells Child Chronic Clinical Clinical Research Controlled Study Data Development Developmental Delay Disorders Diffusion Magnetic Resonance Imaging Drug Exposure Drug usage Epilepsy Equilibrium Exposure to Goals Hippocampus (Brain)Human Hypoxia Impairment Infant Injury Intellectual functioning disability Intervention Learning Levetiracetam Life Long-Term Effects Long-Term Potentiation Magnetic Resonance Imaging Measurement Melatonin Memory Modeling Neonatal Nervous System Physiology Neurons Newborn Infant Outcome Oxidative Stress Pathway interactions Peripheral Pharmaceutical Preparations Pharmacotherapy Phenobarbital Phenytoin Population Pregnancy Rattus Recording of previous events Resolution Risk Rodent Model Safety Seizures Synapses Testing Toxic effect adverse outcome animal imaging base behavior test brain volume clinically relevant cognitive development critical period early life exposure hypoxia neonatorum infancy lamotrigine mature animal medication safety morphometry neonatal period neonatal seizure neonate nervous system disorder neurochemistry neurodevelopmental effect neuroimaging marker neuron apoptosis neurophysiology neuropsychiatric disorder offspring patch clamp postnatal development postnatal period pre-clinical preclinical study prospective synaptogenesis treatment effect valproate

项目摘要

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.

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。