KCNQ channel opener efficacy for neonatal seizures

KCNQ 通道开放剂对新生儿惊厥的疗效

• 批准号: 7130508
• 负责人: EDWARD C COOPER
• 金额: $ 22.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130508
• 关键词: brain; epilepsy; experience; human; hypoxia; model; potassium channel

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）：新生儿癫痫发作是未满足医疗需求的重要领域。癫痫发作在新生儿期比生命中的任何其他时期都更频繁地发生。此外，难治性癫痫发作是新生儿的不祥征兆，与短期发病率和死亡率以及随后的癫痫的重大风险相关。1 - 2%的重症监护室新生儿会出现癫痫发作。20%至40%的足月婴儿在冲浪时癫痫发作，随后出现残疾，这一比例在早产儿中增加到近90%。尽管新生儿癫痫发作通常是脑损伤的症状，如缺氧、缺血性中风、出血或感染，但临床和实验室研究表明，癫痫发作独立地导致新生儿脑损伤和不良发育结局。目前可用的新生儿癫痫发作治疗方法都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产生耐药性的原因之一。新生儿的大脑在神经化学和结构上与成熟的大脑有很大的不同。它是轻度髓鞘化的，GABA抑制性神经传递建立不良，许多局部回路及其突触不成熟。遗传学和新的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神经元回路的过度兴奋方面具有重要作用。当前提案的目标是开始测试以下假设：增加大脑KCNQ通道开放的药物可以终止和预防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，涉及暴露的新生大鼠的促惊厥药物氟或短暂的脑缺氧。这样的体内临床前实验是我们的总体目标，即引入更有效的人类新生儿癫痫发作治疗方法的重要下一步。