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Fluoxetine recovery of synaptic dysfunction following juvenile global cerebral ischemia

氟西汀恢复青少年全脑缺血后突触功能障碍

基本信息

批准号：
10509753
负责人：
Robert M Dietz
金额：
$ 42.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509753
关键词：
Acute Address Adolescent Adult Age-Years Applications Grants Behavior Binding Brain Brain Injuries Cell Death Cerebral Ischemia Cessation of life Child Childhood Chronic Clinical Cognitive Cognitive deficits Communication Data Development Disease model Dose Education Electrophysiology (science)FDA approved Face Fluoxetine Frequencies Functional disorder Genetic Head Heart Arrest Hippocampus (Brain)Hour Human Impaired cognition Impairment Innovative Therapy Intervention Ischemia Knowledge Learning Life Long-Term Potentiation LoxP-flanked allele Memory Memory impairment Methods Modeling Mus Neurologic Neuronal Injury Neurons Outcome Pathway interactions Persons Pharmacology Physiological Physiology Protein Tyrosine Kinase Receptor Signaling Recovery Recovery of Function Reporting Research Research Proposals Role School-Age Population Schools Serotonin Signal Transduction Specificity Stimulus Stroke Survivors Synapses Synaptic plasticity Testing Therapeutic Time TimeLine Translating Translations United States child depression cholinergic cognitive ability cognitive function developmental plasticity early childhood experimental study functional disability functional restoration genetic manipulation improved improved functioning injury and repair innovation interest ischemic injury mature animal mouse model natural hypothermia negative affect neonate neural circuit neuron loss neuronal circuitry neuroprotection neurorestoration neurotropic novel novel strategies prepuberty receptor repaired response reuptake serotonin receptor standard of care synaptic function therapy design translational approach translational potential

项目摘要

ABSTRACT Global cerebral ischemia caused by cardiac arrest results in many neurological sequelae, including deficits in learning and memory. These deficits are as evident in children as they are in adults, though some report that there is improved recovery in the developing brain over time. The resulting neurological sequelae from pediatric cardiac arrest likely arise from both neuronal death and altered physiology in surviving neurons. Surprisingly, while we know a great deal about ischemic consequences in adults, very little is known about the juvenile brain in response to global ischemic insults, thus leading to very few, if any, therapies for children after cardiac arrest. Therefore, we have developed a novel mouse model of juvenile cardiac arrest that mimics very early childhood to address these questions. Our preliminary data suggests that functional impairment in learning and memory occurs in the juvenile brain, followed by recovery at chronic time points. While this recovery is important, we contend that there is a large amount of time in which intervention can occur to maximize the learning potential of children in school age years. A large part of research focuses on discovery of therapeutics to enhance functional recovery. Hence, we have designed an intervention timeline that has the potential to dramatically alter current therapeutic windows. For adults and neonates who suffer global ischemia, the standard of care remains therapeutic hypothermia, or cooling of the head and/or body to limit neuronal injury when started within hours of ischemia. This same strategy does not protect the childhood brain. Additionally, no pharmacologic agents to protect neuronal injury after ischemia have been translated for use in people. Therefore, we have taken a novel approach to improving and restoring function after global cerebral ischemia. This grant application tests the hypothesis that the neurons that survive ischemia have impaired function, and this impairment can be targeted for intervention. Our preliminary data suggests that administration of fluoxetine 7-14 days after ischemic insult can reverse functional impairments. Specifically, there is evidence that fluoxetine increases brain-derived neurotropic factor (BDNF), a molecule that is vital to mechanisms of learning and memory, as well as the BDNF receptor tyrosine kinase B (TrkB), to rescue impaired synaptic plasticity after global cerebral ischemia. We propose experiments using electrophysiology, behavior, pharmacology, genetic manipulation and intracellular signaling interrogation to address the hypothesis: Delayed administration of fluoxetine activates BDNF-TrkB signaling to restore impaired synaptic function and cognitive following juvenile global cerebral ischemia. If the preliminary data presented in this application suggesting delayed administration of fluoxetine reverses functional impairments are supported, then we may be upon a paradigm shifting strategy and high translational potential through extending therapeutic windows after global cerebral ischemia in children through novel neurorestorative strategies, which perhaps, could be extended to adults and neonates as well.

摘要