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：
10085123
负责人：
Patrick Alexander Forcelli
金额：
$ 6.3万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10085123
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 Structure 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 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.

项目概要大脑发育关键时期的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，其中潜在的疾病和治疗两者都可能产生不良影响。一个例子是平衡药物的选择治疗癫痫发作，这是婴儿期最常见的神经系统疾病之一。新生儿癫痫发作是缺氧（或缺氧缺血）后常见；这些癫痫发作通常会积极治疗抗惊厥药物。缺氧引起的癫痫发作与晚年风险显着增加相关癫痫发作，以及严重的发育迟缓和智力障碍。然而，由于结果癫痫发作和药物治疗的结果是混杂的。在本申请中，我们建议评估：(1) 缺氧诱发癫痫发作的效果，(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) 神经保护干预的功效（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 CA1 亚区神经元的记录）和行为（成人学习和记忆测试）婴儿时期接触药物和/或癫痫发作的动物）。我们还将通过以下方式评估药物安全性的生物标志物：动物氧化应激的外周测量和高分辨率磁共振成像遭受这些早年的侮辱。最后，我们将确定我们的神经保护干预措施是否可以改善与癫痫发作和/或药物治疗相关的部分或全部不良后果。