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，药物治疗会对神经系统功能产生不利影响。这对治疗神经系统疾病的治疗构成了挑战治疗两者都可能产生不利影响。一个例子是平衡选择药物的选择癫痫发作的治疗是婴儿期最常见的神经系统疾病之一。新生儿的癫痫发作是缺氧（或缺氧 - 缺血）后常见发生；这些癫痫发作通常会积极地治疗抗惊厥药。缺氧引起的癫痫发作与后来生活的风险大幅增加有关癫痫发作以及重大的发展延迟和智力残疾。但是，结果到期癫痫发作和由于药物疗法引起的结果被混淆。在此应用程序中，我们建议评估：（1）缺氧诱导的癫痫发作的作用，（2）三种最常见的抗塞氏菌药物的作用用于婴儿（苯巴比妥，苯妥英，左乙酰乙酰胺），（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在该水平上影响大脑发育的程度生物化学（评估程序性细胞死亡，氧化应激），神经生理学（斑块钳）来自海马CA1子场中神经元的录音）和行为（成人学习和记忆的测试暴露于药物和/或癫痫发作的动物作为婴儿）。我们还将通过动物的氧化应激和高分辨率磁共振成像的外围测量暴露于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可以改善与癫痫发作和/或药物治疗相关的一些不良结果或全部。