Brain Inflammation in Childhood Epilepsy

儿童癫痫的脑部炎症

• 批准号: 7432575
• 负责人: SOOKYONG KOH
• 金额: $ 16.02万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432575
• 关键词: Acute; Adolescent; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Brain; Brain Injuries; CDKN1A gene; Cells; Cellular Infiltration; Cessation of life; Childhood; Chronic; Class; Code; Complement; Complement Inactivators; Convulsions; Data; Detection; Disease remission; Encephalitis; Epilepsy; Epileptogenesis; Event; Future; Genes; Goals; Hippocampus (Brain); Histocytochemistry; Hour; Human; Hypoxia; In Situ; Inflammation; Inflammatory; Inflammatory Response; Intervention; Isolectin; Kainic Acid; Lead; Life; Link; Long-Term Effects; Long-Term Potentiation; Mediating; Mediator of activation protein; Messenger RNA; Microglia; Minocycline; Modeling; Molecular; Morphology; Neuronal Injury; Neurons; Non-Steroidal Anti-Inflammatory Agents; Numbers; Oligonucleotides; Operative Surgical Procedures; Pathway interactions; Perinatal Hypoxia; Pharmaceutical Preparations; Pilot Projects; Play; Predisposition; Production; Prostaglandin-Endoperoxide Synthase; Protein Analysis; Rattus; Reaction; Recurrence; Role; Seizures; Specimen; Status Epilepticus; System; Testing; Time; Transcript; Transcriptional Activation; Transgenic Mice; Translations; Up-Regulation; Western Blotting; allograft inflammatory factor-1; base; celecoxib; cell injury; cobra venom factor; cyclooxygenase 2; cytokine; day; density; design; early experience; functional group; immunocytochemistry; inhibitor/antagonist; neuronal excitability; oncoprotein p21; postnatal; ranpirnase; response

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.

描述（由申请人提供）：慢性癫痫通常始于生命早期的孤立，长时间的惊厥，随后是一段缓解期;癫痫发作然后重新出现，可能变得难以治愈。最初癫痫发作后的缓解期为癫痫发作和不可逆脑损伤之前的干预提供了一个机会窗口。这项建议的具体重点是调查脑炎症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癫痫作用。我们已经开发了一个“两次打击”癫痫发作模型，证明了早期癫痫发作，而不会引起明显的细胞损伤，增加癫痫发作和癫痫诱导的神经元损伤的易感性在成年期。为了阐明发育中大脑癫痫发作与晚发型癫痫发作之间的联系机制，我们使用了高密度寡核苷酸基因阵列，并描述了早期癫痫发作后发生的分子级联反应，这些分子级联反应可能是后来癫痫发作易感性增加的基础。我们的初步结果表明，小胶质细胞的激活和随后的细胞因子和补体的增加可能是糖尿病诱导的炎症反应的关键起始事件。并行使用两个癫痫发作模型，围产期缺氧和早期生活红藻氨酸（KA），我们建议测试以下假设：由早期生活癫痫发作引起的炎症反应引发发育中的大脑，使小胶质细胞被修改，导致快速再激活的第二次癫痫发作在成年期。目的1将确定是否KA诱导的癫痫持续状态在成年后的小胶质细胞的激活和增殖增加与早期生活癫痫发作的经验之前的大鼠。目的2将确定早期癫痫发作的长期致敏作用是否可以通过抗炎药物的后处理来阻断。目的3：利用寡核苷酸基因阵列研究癫痫早期启动效应中的特异性炎症通路。目的4将使用具有GFP标记的小胶质细胞的转基因小鼠来评估早期生命癫痫发作对随后KA刺激诱导的小胶质细胞活化和增殖的长期影响。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。这些目的旨在共同检验早期癫痫发作的致癫痫效应是由脑炎症介导的中心假设。