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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：
8492175
负责人：
ANNE M COMI
金额：
$ 33.1万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492175
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.

描述（由申请人提供）：新生儿中风影响4000名足月新生儿中的一名，并经常导致认知障碍。新生儿中风表现为癫痫发作，随后数月给予抗惊厥药（通常为苯巴比妥）。我们的中心假设是新生儿卒中后海马神经发生受损导致认知功能障碍，抗惊厥药物调节卒中后神经发生和认知结果。更具体地说，我们假设抗惊厥药物增加GABA信号减少海马神经发生和损害认知结果，和抗惊厥药物抑制组蛋白脱乙酰酶增加海马神经发生和改善认知结果。方法：我们将使用最近开发的缺血性癫痫发作和脑损伤的未成熟小鼠模型。P12 CD 1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的认知功能、萎缩和新生海马细胞的成熟。在一个单独的动物队列中，我们将在一个新的空间任务后，利用Arc-BrdU-NeuN共标记评估中风后新生神经元的整合。我们将确定长期给药的药物，增强GABA的传输或抑制组蛋白去乙酰化酶后萎缩，神经发生，认知障碍和慢性癫痫发作在这个模型中的影响。意义：未成熟大脑中的中风导致认知障碍，通常持续到成年期。即使是部分减少认知障碍的干预措施也会显著改善生活质量，降低国家医疗保健成本。这项工作将确定哪种抗惊厥药物更有可能改善新生儿卒中后的认知结果，反之，应避免使用哪种抗惊厥药物。这项工作也将揭示有关GABA和组蛋白去乙酰化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科医生的背景，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。