The Epileptogenic Effect of Perinatal Hypoxia

与缺氧性脑病相关的新生儿癫痫发作对常规AED治疗无效， 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，并且作为一种特殊的神经系统， 活动依赖性突触发生和皮层神经元所需的生理过度兴奋的功能 发展在过去的15年里，这项研究计划已经产生了一个可靠的新生儿啮齿动物模型， 缺氧性癫痫发作，确定了特定的年龄依赖性机制，验证了年龄特异性表达， 这些目标在人类新生儿皮层组织，并执行治疗试验，在大鼠靶向 这些机制，使用临床可用的药物。在新生儿癫痫的啮齿动物模型中， 显示在癫痫发作后全身给予谷氨酸受体拮抗剂48小时， 预防长期后果，因此可能是疾病修饰。本提案将重点 在这一发作后立即和早期窗口，以确定现有的快速翻译后修饰， 蛋白质和调节机制控制蛋白质从预先存在的mRNA的翻译， 是可预防的和/或可逆的。 目标1.为了确定电刺激诱导的离子型谷氨酸受体功能变化的时间过程， 以及它们是否与受体亚单位的翻译后修饰有关。 目标二。确定AMPAR和NMDAR的翻译后修饰是否仅仅是相关的 或在体内和体外与缺氧性惊厥诱导的癫痫发生机制相关。 Aiim 3.为了确定哺乳动物雷帕霉素靶蛋白（mTOR）信号通路是否代表了一种免疫抑制剂， 用于预防缺氧性癫痫引起的过度兴奋的治疗靶点。 目标4。为了继续我们对谷氨酸受体表达的成熟模式的人体组织研究， 研究mTOR通路激活是否可以在死后人脑组织中检测到， 缺氧足月儿 我们的初步结果表明，许多这些早期癫痫发作诱导的蛋白质变化是惊人的， 类似于在突触可塑性模型中观察到的那些。这一提议的总体假设是， 这些早期变化代表了抗癫痫发生的干预点，即使在癫痫发作已经被控制之后， 诱导。该资助期的主要重点是在这48小时窗口内确定这些分子靶点， 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.