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）：新生儿癫痫发作是医疗需求未得到满足的一个重要领域。新生儿期癫痫发作的发生率比生命中任何其他时期都要高。此外，难治性癫痫发作对于新生儿来说是一个不祥的征兆，与短期发病率和死亡率以及随后的癫痫的巨大风险相关。入住重症监护病房的新生儿中有 1% 到 2% 出现癫痫发作。 20% 至 40% 的足月婴儿在出现癫痫发作后会出现残疾，而早产儿中这一比例几乎增加到 90%。尽管新生儿癫痫发作通常是由于缺氧、缺血性中风、出血或感染等脑损伤症状而出现，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果。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产生耐药性的原因之一。新生儿大脑在神经化学和结构上与成熟大脑有很大不同。它有轻度髓鞘化，GABA 抑制性神经传递尚未建立，许多局部回路及其突触不成熟。遗传和新的细胞生物学数据表明，KCNQ 电压门控钾通道在预防未成熟大脑神经元回路过度兴奋方面具有重要作用。当前提案的目标是开始检验以下假设：增加大脑 KCNQ 通道开口的药物可以终止并预防新生儿癫痫发作的复发。我们建议通过使用已建立的新生儿癫痫发作啮齿动物模型进行实验来做到这一点，其中包括将新生大鼠暴露于促惊厥药物氟洛西或短暂的脑缺氧。这种体内临床前实验是实现我们总体目标的重要一步，即为人类新生儿癫痫引入更有效的治疗方法。