KCNQ channel opener efficacy for neonatal seizures

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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.