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

• 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
• 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

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 由心脏骤停引起的全脑缺血导致许多神经系统后遗症，包括神经功能缺损。 学习和记忆。这些缺陷在儿童和成人中同样明显，尽管有些报告说， 随着时间的推移，发育中的大脑的恢复有所改善。神经系统后遗症 小儿心脏骤停可能由神经元死亡和存活神经元的生理改变引起。 令人惊讶的是，虽然我们对成人缺血性后果了解很多，但对缺血性心脏病的影响却知之甚少。 青少年大脑对全面缺血性损伤的反应，因此导致很少，如果有的话，治疗儿童后， 心脏骤停因此，我们开发了一种新的幼年心脏骤停小鼠模型， 儿童早期来解决这些问题。我们的初步数据表明， 学习和记忆发生在青少年的大脑中，然后在慢性时间点恢复。虽然这 恢复是重要的，我们认为，有大量的时间，其中干预可以发生， 最大限度地发挥学龄儿童的学习潜力。很大一部分研究集中在发现上 来增强功能恢复因此，我们设计了干预时间轴， 有可能极大地改变目前的治疗窗口。对于患有全球性疾病的成人和新生儿， 对于缺血，护理标准仍然是治疗性低温，或头部和/或身体的冷却，以限制 在缺血数小时内开始的神经元损伤。同样的策略并不能保护儿童的大脑。 此外，还没有保护缺血后神经元损伤的药理学试剂被翻译用于治疗缺血性脑损伤。 人因此，我们采取了一种新的方法来改善和恢复全脑缺血后的功能， 缺血这项拨款申请测试了缺血后存活的神经元受损的假设， 功能，这种损害可以有针对性地进行干预。我们的初步数据显示， 缺血性损伤后7 - 14天给予氟西汀可以逆转功能障碍。具体地说， 有证据表明，氟西汀增加脑源性神经营养因子（BDNF），一种对 学习和记忆的机制，以及BDNF受体酪氨酸激酶B（Trk B），以拯救 全脑缺血后突触可塑性受损。我们建议使用电生理学进行实验， 行为学、药理学、遗传操作和细胞内信号转导， 假设：延迟给予氟西汀激活BDNF-TrkB信号传导以恢复受损的突触 功能和认知功能的影响。如果本报告中提供的初步数据 支持延迟给予氟西汀逆转功能损伤的应用， 那么我们可能会通过扩展， 儿童全脑缺血后的治疗窗口，通过新的神经恢复策略， 也许可以扩展到成人和新生儿。