Anticonvulsants, ischemic seizures and regeneration in the immature brain

抗惊厥药、缺血性癫痫发作和未成熟大脑的再生

基本信息

批准号：
8289545
负责人：
ANNE M COMI
金额：
$ 34.3万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289545
关键词：
Acute Address Adult Affect Animals Anticonvulsants Atrophic Birth Brain Brain Injuries Bromodeoxyuridine CDK6-associated protein p18 Cells Childhood Chronic Clinical Cognition Cognitive Cognitive deficits Dose Glutamates Goals Health Health Care Costs Hippocampus (Brain)Histone Deacetylase Histone deacetylase inhibition Histones Human Impaired cognition Infarction Injection of therapeutic agent Injury Intervention Ischemia Label Learning Ligation Measures Mediating Modeling Mus Natural regeneration Neonatal Neurologist Neurons Newborn Infant Outcome Pharmaceutical Preparations Phenobarbital Play Process Production Protocols documentation Quality of life Recovery Research Role Scientist Seizures Serum Severities Short-Term Memory Signal Transduction Stroke Synaptic Transmission Term Birth Testing Training Weaning Work analog cerebral atrophy clinically relevant cognitive function cognitive recovery cohort dentate gyrus experience gamma-Aminobutyric Acid granule cell hippocampal atrophy improved innovation insight mouse model neonate neurogenesis newborn neuron novel post stroke postnatal prevent response sham surgery transmission process

项目摘要

DESCRIPTION (provided by applicant): Neonatal stroke affects one in 4000 term births and frequently results in cognitive impairments. Neonatal strokes present with seizures, and anticonvulsants (usually phenobarbital) are administered for months afterward. Our central hypothesis is that impaired hippocampal neurogenesis after neonatal stroke contributes to cognitive dysfunction, and anticonvulsants modulate both post-stroke neurogenesis and cognitive outcome. More specifically we hypothesize that anticonvulsants increasing GABA signaling decrease hippocampal neurogenesis and impair cognitive outcome, and anticonvulsants inhibiting histone deacetylase increase hippocampal neurogenesis and improve cognitive outcome. Approach: We will use a recently developed immature mouse model of ischemic seizures and brain injury. P12 CD1 mice will receive unilateral carotid ligation and BrdU labeling, and we will measure cognitive function, atrophy, and maturation of newborn hippocampal cells in the same animals. In a separate cohort of animals we will assess post-stroke integration of newborn neurons utilizing Arc-BrdU-NeuN co-labeling after a novel spatial task. We will determine the impact of chronically administered drugs that enhance GABA transmission or inhibit histone deacetylase upon atrophy, neurogenesis, cognitive impairment and chronic seizures in this model. Significance: Stroke in the immature brain causes cognitive impairment that often persists into adulthood. An intervention providing even partial reduction of cognitive impairment would result in significantly improved quality of life and decreased national healthcare costs. This work will determine which anticonvulsant is more likely to improve cognitive outcome after neonatal stroke and conversely which anticonvulsant should be avoided. This work will also reveal mechanistic insights regarding the role of GABA and histone deacetylase in neurogenesis and recovery after neonatal stroke. The background, training, and experience of the PI as a clinician scientist and pediatric neurologist make her uniquely suited and highly motivated to carry out this important research. PUBLIC HEALTH RELEVANCE: Neonatal stroke is an important cause of learning problems that often last into adulthood. Because neonatal stroke presents with seizures, seizure medications are given and usually continued for months afterward. This work will provide important insights as to which seizure medications are more likely to improve new cell birth and learning after neonatal stroke and which should be avoided. The studies will also inform our understanding of processes important to new cell birth and cognitive outcome in the immature brain after neonatal stroke.

描述（由申请人提供）：新生儿中风影响四千分之一的足月产儿，并经常导致认知障碍。新生儿中风伴有癫痫发作，几个月后需要服用抗惊厥药（通常是苯巴比妥）。我们的中心假设是，新生儿中风后海马神经发生受损会导致认知功能障碍，而抗惊厥药可调节中风后神经发生和认知结果。更具体地说，我们假设增加 GABA 信号传导的抗惊厥药会减少海马神经发生并损害认知结果，而抑制组蛋白脱乙酰酶的抗惊厥药会增加海马神经发生并改善认知结果。方法：我们将使用最近开发的缺血性癫痫和脑损伤的未成熟小鼠模型。 P12 CD1 小鼠将接受单侧颈动脉结扎和 BrdU 标记，我们将测量同一动物中新生海马细胞的认知功能、萎缩和成熟。在另一组动物中，我们将在一项新的空间任务后利用 Arc-BrdU-NeuN 联合标记来评估中风后新生神经元的整合。我们将确定长期服用增强 GABA 传递或抑制组蛋白脱乙酰酶的药物对该模型中的萎缩、神经发生、认知障碍和慢性癫痫发作的影响。意义：未成熟大脑中的中风会导致认知障碍，这种障碍通常会持续到成年期。即使是部分减少认知障碍的干预措施也将显着提高生活质量并降低国家医疗保健成本。这项工作将确定哪种抗惊厥药更有可能改善新生儿中风后的认知结果，以及相反应避免哪种抗惊厥药。这项工作还将揭示有关 GABA 和组蛋白脱乙酰酶在新生儿中风后神经发生和恢复中的作用的机制见解。 PI 作为临床科学家和儿科神经病学家的背景、培训和经验使她非常适合并非常积极地开展这项重要的研究。公共卫生相关性：新生儿中风是导致学习问题的一个重要原因，这种问题通常会持续到成年期。由于新生儿中风伴有癫痫发作，因此需要给予癫痫药物治疗，并且通常会持续数月。这项工作将为哪些癫痫药物更有可能改善新生儿中风后新细胞的产生和学习以及哪些药物应该避免提供重要见解。这些研究还将帮助我们了解新生儿中风后未成熟大脑中新细胞诞生和认知结果的重要过程。