The Epileptogenic Effect of Perinatal Hypoxia

与缺氧性脑病相关的新生儿癫痫发作对传统的AED治疗是困难的， 与长期神经发育迟缓、认知障碍和癫痫有关。新生儿 大脑从根本上不同于成人的大脑，作为一种 活动依赖性突触发生和皮层所需的生理性高兴奋性的功能 发展。在过去的15年里，这个研究项目已经产生了一个可靠的新生儿啮齿动物模型 低氧惊厥，确定特定的年龄依赖机制，验证年龄特异性的表达 这些靶点在人类新生儿皮质组织中，并在大鼠中进行靶向治疗试验 这些机制，使用的是临床上可用的药物。在我们新生儿癫痫的啮齿动物模型中，我们有 研究表明，癫痫发作后全身应用谷氨酸受体拮抗剂48小时可以 防止长期后果，因此可能是疾病的改良剂。本提案将把重点放在 在这个即刻和早期的发作后窗口，以确定现有的快速翻译后修改 蛋白质和调控蛋白质翻译的调节机制，可能 是可预防的和/或可逆的。 目的1.确定癫痫发作后离子型谷氨酸受体功能改变的时程。 以及它们是否与受体亚基的翻译后修饰有关。 目的2.确定AMPAR和NMDAR中的翻译后修饰是否仅仅相关 或在体内和体外与缺氧性癫痫诱导的癫痫发生有关的机制。 为了确定雷帕霉素(MTOR)信号通路的哺乳动物靶点是否代表一种 预防缺氧性癫痫高兴奋性的治疗靶点。 目的4.继续我们的人体组织对谷氨酸受体表达和成熟模式的研究 研究是否可以在死后的人脑组织中检测到mTOR通路的激活 缺氧足月婴儿。 我们的初步结果显示，这些早期癫痫发作引起的蛋白质变化中的许多是惊人的 类似于在突触可塑性模型中观察到的。这项提议的总体假设是 这些早期的变化代表了抗癫痫发生的干预点，即使在癫痫发作之后也是如此 诱导性。此资助期的一个主要焦点是在48小时窗口中确定这些分子靶标 用已知对这些靶点具有调节活性的现成药物进行干预。

Neonatal seizures associated with hypoxic encephalopathy are refractory to conventional AED therapy, and are associated with long term neurodevelopmental delay, cognitive impairment and epilepsy. The newborn brain is fundamentally different from the adult brain, and is uniquely susceptible to epileptic stimuli as a function of physiological hyperexcitability required for activity dependent synaptogenesis and cortical development. In the prior 15 years, this research program has generated a reliable rodent model of neonatal hypoxic seizures, identified specific age-dependent mechanisms, validated the age specific expression of these targets in human neonatal cortical tissue, and executed therapeutic trials in the rat targeted towards these mechanisms, using clinically available drugs. In our rodent models of neonatal seizures, we have shown that systemic administration of glutamate receptor antagonists for 48 hrs following seizures can prevent the long term consequences, and hence may be disease modifying. The present proposal will focus on this immediate and early post seizure window to identify rapid post-translational modifications of existing protein and regulatory mechanisms governing the translation of protein from of pre-existing mRNA that may be preventable and/or reversible. Aim 1. To determine the time course of seizure-induced changes in ionotropic glutamate receptor function, and whether they are associated with post-translational modification of receptor subunits. Aim 2. To establish whether post-translational modifications in AMPARs and NMDARs are merely correlated or mechanistically related to in hypoxic seizure-induced epileptogenesis in vivo and in vitro. Aiim 3. To determine whether the mammalian target of rapamycin (mTOR) signaling pathway represents a therapeutic target for prevention of hypoxic-seizure induced hyperexcitability. Aim 4. To continue our human tissue study of maturational patterns of glutamate receptor expression and investigate whether mTOR pathway activation can be detected in postmortem human brain tissue from hypoxic term infants. Our preliminary results reveal that many of these early seizure induced changes in proteins are strikingly similar to those observed in models of synaptic plasticity. The overall hypothesis of this proposal is that these early changes represent intervention points for antiepileptogenesis, even after the seizures have been induced. A major focus for this funding period is to identify these molecular targets in this 48 hr window and intervene with available off-the-shelf drugs that are known to have modulatory activity at these targets.