Brain Inflammation in Childhood Epilepsy

描述（由申请人提供）：慢性癫痫通常在生命早期以孤立的、长时间的抽搐开始，随后是一段缓解期；然后癫痫再次出现，并可能变得难治性。最初癫痫发作后的这段缓解期为在癫痫发作和不可逆转的脑损伤之前进行干预提供了机会。本研究的重点是研究脑炎在儿童癫痫中的作用，并确定抗炎治疗是否可以逆转早期癫痫发作的致痫作用。我们已经开发了一种“两次发作”的癫痫模型，证明早期的癫痫发作，没有引起明显的细胞损伤，增加了癫痫发作的易感性，并在成年期引起癫痫引起的神经元损伤。为了阐明发育中的大脑癫痫与晚发性癫痫之间的联系机制，我们使用高密度寡核苷酸基因阵列并表征了早期癫痫发作后发生的分子级联反应，这可能是后来癫痫易感性增加的基础。我们的初步结果表明，小胶质细胞的激活和随后细胞因子和补体的增加可能是癫痫诱发炎症反应的关键启动事件。利用两种平行的癫痫发作模型，围产期缺氧和生命早期的kainic酸（KA），我们提出验证以下假设：由生命早期癫痫发作引起的炎症反应启动了发育中的大脑，使小胶质细胞被修改，导致成年期第二次癫痫发作时快速重新激活。目的1将确定ka诱导的成年期癫痫持续状态是否会在早期癫痫发作的大鼠中增加小胶质细胞的激活和增殖。目的2将确定早期癫痫发作的长期致敏效应是否可以通过抗炎药物治疗后阻断。目的3将使用寡核苷酸基因阵列识别涉及早期癫痫发作启动效应的特定炎症途径。目的4将利用转基因小鼠gfp标记的小胶质细胞，评估早期癫痫对KA癫痫诱导的小胶质细胞激活和增殖的长期影响。我们将通过检查人类癫痫手术标本中的炎症基因来测试我们数据的人类相关性。总之，这些目的是为了验证中心假设，即早期癫痫发作的致痫效应是由脑部炎症介导的。

DESCRIPTION (provided by applicant): Chronic epilepsy often starts with an isolated, prolonged convulsion in early life followed by a period of remission; seizures then re-emerge and may become intractable. This period of remission following an initial seizure provides a window of opportunity for intervention prior to the onset of epilepsy and irreversible brain damage. The specific focus of this proposal is to investigate the role of brain inflammation in childhood epilepsy and to determine whether anti-inflammatory therapy can reverse the epileptogenic effect of early- life seizures. We have developed a "two-hit" seizure model demonstrating that an early life seizure, without causing overt cellular injury, increases susceptibility to seizures and to seizure-induced neuronal injury in adulthood. To elucidate the mechanisms linking seizures in the developing brain to later-onset epilepsy, we have used high-density oligonucleotide gene arrays and characterized the molecular cascades occurring after early life seizures that may underlie later increased seizure susceptibility. Our preliminary results indicate that activation of microglia and subsequent increases in cytokines and complements may be the key initiating events for seizure-induced inflammatory responses. Using two seizure models in parallel, perinatal hypoxia and early-life kainic acid (KA), we propose to test the following hypothesis: the inflammatory reaction provoked by early life seizures primes the developing brain so that microglia are modified, leading to rapid reactivation by a second seizure in adulthood. Aim 1 will establish whether microglial activation and proliferation after KA-induced status epilepticus in adulthood is increased in rats with prior experience of early-life seizures. Aim 2 will determine if this long- term sensitizing effect of early-life seizures can be blocked by post-treatment with anti-inflammatory drugs. Aim 3 will identify specific inflammatory pathways involved in the priming effect of early-life seizures using oligonucleotide gene arrays. Aim 4 will evaluate the long-term effect of early life seizures on subsequent KA seizure-induced activation and proliferation of microglia using transgenic mice with GFP-tagged microglia. We will test the human relevance of our data by examining inflammatory genes in human epilepsy surgery specimen. Together these Aims are designed to test the central hypothesis that the epileptogenic effect of early life seizures is mediated by brain inflammation.