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）：新生儿中风会影响4000个学期的出生，经常会导致认知障碍。随后几个月，对存在癫痫发作的新生儿中风和抗惊厥药（通常是苯巴比妥）进行了。我们的中心假设是，新生儿中风后的海马神经发生受损会导致认知功能障碍，而抗惊厥药则调节了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降低海马神经发生并损害认知结果，而抑制组蛋白脱乙酰基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发作和脑损伤的小鼠模型。 P12 CD1小鼠将获得单侧颈动脉连接和BRDU标记，我们将测量同一动物中新生儿海马细胞的认知功能，萎缩和成熟。在另一批动物中，我们将在新的空间任务后使用Arc-Brdu-Neun共同标记来评估新生神经元的冲程后整合。我们将确定在该模型中增强GABA传播或抑制组蛋白脱乙酰基酶对组蛋白脱乙酰基酶的影响，以增强组蛋白脱乙酰基酶对此模型中的萎缩，神经发生，认知障碍和慢性癫痫发作。意义：未成熟大脑中的中风会导致认知障碍，而认知障碍通常会持续到成年。一项干预措施甚至可以部分降低认知障碍，将显着改善生活质量并降低国家医疗保健成本。这项工作将确定新生儿中风后哪种抗惊厥药更有可能改善认知结果，相反，应避免哪种抗惊厥药。这项工作还将揭示有关GABA和组蛋白脱乙酰基酶在新生儿中风后神经发生和恢复中的作用的机理见解。 PI作为临床医学家和儿科神经科医生的背景，培训和经验使她非常适合和高度动力进行这项重要的研究。