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:
  • 金额:
    $ 42.76万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Robert M Dietz其他文献

Late initiation of therapeutic hypothermia: not the new standard of care
晚期开始低温治疗:不是新的护理标准
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Stephanie L. Bourque;Robert M Dietz
  • 通讯作者:
    Robert M Dietz
Relative contributions of zinc and calcium to acute injury to hippocampal CA1 neurons
  • DOI:
  • 发表时间:
    2010-06
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Robert M Dietz
  • 通讯作者:
    Robert M Dietz
Antenatal magnesium for preterm delivery reduces risk of cerebral palsy among surviving very preterm infants
早产的产前镁可降低幸存的极早产儿脑瘫的风险
  • DOI:
    10.1111/apa.14116
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Megan E Paulsen;Robert M Dietz
  • 通讯作者:
    Robert M Dietz
Potential Adjuncts to Therapeutic Hypothermia to Mitigate Multiorgan Injury in Perinatal Hypoxia-Ischemia.
低温治疗的潜在辅助手段可减轻围产期缺氧缺血的多器官损伤。
  • DOI:
    10.1542/neo.24-12-e771
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Megan J Turner;Robert M Dietz
  • 通讯作者:
    Robert M Dietz

Robert M Dietz的其他文献

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{{ truncateString('Robert M Dietz', 18)}}的其他基金

TRPM2 channels and synaptic dysfunction following ischemic injury in the developing brain.
发育中大脑缺血损伤后的 TRPM2 通道和突触功能障碍。
  • 批准号:
    9386009
  • 财政年份:
    2017
  • 资助金额:
    $ 42.76万
  • 项目类别:
TRPM2 channels and synaptic dysfunction following ischemic injury in the developing brain.
发育中大脑缺血损伤后的 TRPM2 通道和突触功能障碍。
  • 批准号:
    10197230
  • 财政年份:
    2017
  • 资助金额:
    $ 42.76万
  • 项目类别:

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