KCNQ channel opener efficacy for neonatal seizures

描述（由申请人提供）：新生儿癫痫发作是未满足医疗需求的一个重要领域。癫痫发作发生在新生儿时期比生命中的任何其他时期都要频繁得多。此外，难治性癫痫发作是新生儿的不祥之兆，与短期发病率和死亡率以及随后的癫痫的重大风险相关。入住重症监护病房的新生儿中有1%至2%经历过癫痫发作。有20%至40%的足月儿因癫痫发作而致残，而在早产儿中，这一比例增加到近90%。虽然新生儿癫痫发作通常作为脑损伤的症状出现，如缺氧、缺血性中风、出血或感染，但临床和实验室研究表明，癫痫发作是新生儿脑损伤和不良发育结局的独立因素。目前治疗新生儿癫痫发作的药物都是通过动物模型和成人临床试验开发的。这可能是新生儿癫痫发作经常对药物治疗产生抗药性的原因之一。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，GABA抑制性神经传递不完善，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电压门控钾通道在防止未成熟大脑神经元回路的高兴奋性中起重要作用。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。我们建议通过使用已建立的啮齿动物新生儿癫痫模型进行实验，包括将新生大鼠暴露于抗惊厥药物氟醚或短暂性脑缺氧。这种体内临床前实验是实现我们为人类新生儿癫痫发作引入更有效治疗的总体目标的重要下一步。

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.