KCNQ channel opener efficacy for neonatal seizures

KCNQ 通道开放剂对新生儿惊厥的疗效

基本信息

批准号：
7286871
负责人：
EDWARD C COOPER
金额：
$ 17.57万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7286871
关键词：
Adult Animal Model Area Behavior Behavioral Benzodiazepines Biological Brain Brain Hypoxia Cells Cerebral Palsy Chromosome Pairing Chronic Clinical Clinical Trials Cognitive deficits Data Development Disabled Persons Dose Drug resistance Drug usage Encephalopathies Epilepsy Europe Exhibits Exposure to Familial benign neonatal epilepsy Flurothyl Genetic Goals Hemorrhage Human Hypoxia Infant Infection Inherited Intensive Care Units Ischemic Stroke Laboratory Study Life Medical Methods Modeling Morbidity - disease rate Mutation N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester Neonatal Neonatal Brain Injury Neurons Newborn Infant Opioid Analgesics Outcome Partial Epilepsies Perinatal Pharmaceutical Preparations Phenobarbital Phenytoin Potassium Channel Predisposition Premature Infant Preparation Rattus Recurrence Refractory Research Personnel Risk Rodent Rodent Model Role Seizures Severities Staging Subclinical Seizures Symptoms Synapses Syndrome Testing Time Voltage-Gated Potassium Channel Week day drug efficacy experience flupirtine gamma-Aminobutyric Acid handicapping condition in vivo kainate mortality neonatal exposure neonate neuron apoptosis neurotransmission pre-clinical preclinical study prevent programs pup research study transcriptional coactivator p75 young adult

项目摘要

DESCRIPTION (provided by applicant): Neonatal seizures represent an important area of unmet medical need. Seizures occur much more frequently in the neonatal period than at any other time of life. Moreover, refractory seizures are an ominous sign in a newborn infant, associated with substantial risk of short term morbidity and mortality and subsequent epilepsy. Between 1 and 2% of neonates admitted to the intensive care unit experience seizures. Between 20 and 40% of term infants who surfer seizures are subsequently handicapped and this increases to almost 90% in preterm infants. Although neonatal seizures often arise as symptoms of brain insult such as hypoxia, ischemic stroke, hemorrhage, or infection, clinical and laboratory studies indicate that seizures independently contribute to neonatal brain injury and poor developmental outcomes. Currently available treatments for neonatal seizures all involve drugs developed using animal models and clinical trials in adults. This is likely one of the reasons why neonatal seizures are very frequently resistant to drug treatment. The neonatal brain is very different from mature brain, neurochemically and structurally. It is lightly myelinated, GABA inhibitory neurotransmission is poorly established, and many local circuits and their synapses are immature. Genetic and new cell biological data indicate that KCNQ voltage-gated potassium channels have an important role in preventing hyperexcitability in neuronal circuits in the immature brain. The goal of the current proposal is to begin to test the following hypothesis: drugs that increase the openings of brain KCNQ channels can terminate and prevent the recurrence of neonatal seizures. We propose to do this through experiments using established rodent models of neonatal seizures, that involve exposure of neonatal rats to the proconvulsant drug flurothyl or to transient brain hypoxia. Such in vivo preclinical experiments are an essential next step toward our overall goal toward introduction of more effective treatments for neonatal seizures in humans.

描述（由申请人提供）：新生儿癫痫发作代表了未满足医疗需求的重要领域。在新生儿时期，癫痫发作的发生频率要比生命的任何其他时期都要高得多。此外，难治性癫痫发作是一个新生婴儿的不祥迹象，与短期发病率和死亡率以及随后的癫痫病的重大风险有关。在重症监护室经历癫痫发作的1-2％的新生儿中。随后，在冲浪者癫痫发作的患者中，有20％到40％的婴儿在早产儿中增加到近90％。尽管新生儿癫痫发作通常是作为脑损伤的症状（例如缺氧，缺血性中风，出血或感染）的症状，但临床和实验室研究表明，癫痫发作独立有助于新生儿脑损伤和发育不良。目前针对新生儿癫痫发作的可用治疗方法均涉及使用动物模型和成人临床试验开发的药物。这可能是新生儿癫痫发作经常对药物治疗具有抗性的原因之一。新生儿大脑在神经化学上和结构上与成熟的大脑大不相同。它被轻微髓鞘，GABA抑制性神经传递的确定性很差，许多局部电路及其突触不成熟。遗传和新细胞生物学数据表明，KCNQ电压门控钾通道在防止未成熟大脑中神经元电路过度兴奋中具有重要作用。当前建议的目的是开始检验以下假设：增加脑KCNQ通道开口的药物可以终止并防止新生儿癫痫发作的复发。我们建议通过实验使用已建立的新生儿癫痫发作的啮齿动物模型来做到这一点，该模型涉及新生大鼠暴露于proconvulsant flurothyl或瞬时脑缺氧。这种体内临床前实验是朝着我们为引入人类新生儿癫痫发作的更有效治疗的总体目标迈出的重要下一步。