GABA-A Receptor Rescue as a Neuroprotective Strategy in Cerebral Ischemia

GABA-A 受体拯救作为脑缺血的神经保护策略

基本信息

  • 批准号:
    7501939
  • 负责人:
  • 金额:
    $ 33.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-30 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Each year approximately 500,000 people suffer from cardiac arrest in the United States, an event associated with poor neurological outcome. Despite intense research over the past 50 years, there are no pharmacological interventions that have proven successful in improving survival and outcome. A hallmark of ischemia-induced neuronal death is excessive release of glutamate leading to excitotoxicity. Unfortunately, glutamate antagonists have proven unsuccessful in humans, predominantly due to side effects. The logical alternative approach would be to apply compounds that activate GABA-A receptors (GABA-A R) in order to counteract excessive glutamate release and excitotoxicity. Interestingly, GABAergic compounds have yielded disappointingly variable results. Recent data has demonstrated that ischemia results in a rapid loss of GABA-A R protein, indicating that the ischemia-induced decrease in GABA-A R protein may cause a decrease in efficacy of GABA-potentiating compounds. Therefore, a treatment that stabilizes GABA-A R protein and function during an ischemic event is an appealing and exciting new approach to neuroprotection. In order to obtain electrophysiological recordings of neuronal GABA-A R function following ischemia, we have developed a cerebellar neuronal culture model. We will use a combination of methods, most notably whole-cell voltage- clamp recordings of synaptic (mIPSCs) and total GABA-A R activity (Current in response to exogenously applied saturating GABA) to confirm and extend upon our preliminary observation that ischemia causes a reduction in functional GABA-A Rs and importantly that ALLO prevents this ischemia-induced loss of function. This RO1 application will test four specific hypotheses 1) that ALLO prevents ischemia-induced reduction in functional GABA-A R, thereby protecting PCs from ischemia. 2) ALLO prevents ischemia-induced reduction in GABA-A R function by maintaining PKC activity and phosphorylation of GABA-A Rs during ischemia. 3) ALLO stabilizes GABA-A R protein during ischemia by preventing proteosome-dependent degradation of GABA-A receptor protein following ischemia and finally 4) that the ALLO-induced protection of GABA-A R function occurs in intact animals exposed to global ischemia (cardiac arrest). Our findings will begin to elucidate the cellular mechanisms of ALLO neuroprotection of PCs and determine molecular pathways that may represent novel targets for neuroprotection.
描述(由申请人提供):在美国,每年约有500,000人患有心脏骤停,这一事件与不良的神经系统结果有关。尽管在过去的50年中进行了深入的研究,但没有证明在改善生存和结果方面成功的药理学干预措施。缺血引起的神经元死亡的标志是谷氨酸过度释放导致兴奋性毒性。不幸的是,谷氨酸拮抗剂在人类中证明没有成功,主要是由于副作用。逻辑替代方法是应用激活GABA-A受体(GABA-A R)的化合物,以抵消过度的谷氨酸释放和兴奋性。有趣的是,GABA能化合物产生了令人失望的可变结果。最近的数据表明,缺血会导致GABA-A R蛋白的迅速丧失,表明缺血诱导的GABA-A R蛋白降低可能导致GABA-局势化合物的疗效降低。因此,在缺血性事件中稳定GABA-A R蛋白和功能的治疗方法是一种吸引人而令人兴奋的神经保护方法。为了获得缺血后神经元GABA-A R功能的电生理记录,我们开发了小脑神经元培养模型。我们将结合使用突触(MIPSC)和总GABA-A R活性的全细胞电压 - 夹具记录(响应于外源应用饱和GABA的电流),以确认并扩展了我们的初步观察结果,这些观察值会导致功能性GABA-A RS损失的功能损失和重要的功能,从而降低了该功能的功能。该RO1应用将测试四个特定假设1)Allo可防止缺血引起的功能性GABA-A R的降低,从而保护PC免受缺血保护。 2)Allo通过在缺血期间维持PKC活性和GABA-A RS的磷酸化来防止缺血诱导的GABA-A R功能降低。 3)Allo通过防止缺血后的蛋白体依赖性降解GABA-A受体蛋白的蛋白体依赖性降解,而稳定在缺血后的GABA-A R蛋白稳定,最后是4)4)4)在暴露于全球性局部缺血(心脏骤停)的完整动物中,同种诱导的GABA-A R功能的保护发生在完整的动物中。我们的发现将开始阐明PC的Allo神经保护的细胞机制,并确定可能代表神经保护的新靶标的分子途径。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Paco S Herson其他文献

Paco S Herson的其他文献

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{{ truncateString('Paco S Herson', 18)}}的其他基金

Vascular mechanisms of sepsis-induced cognitive dysfunction
脓毒症所致认知功能障碍的血管机制
  • 批准号:
    10681857
  • 财政年份:
    2023
  • 资助金额:
    $ 33.69万
  • 项目类别:
New approach to sustained neuroprotection and enhanced recovery following acute ischemic stroke
急性缺血性中风后持续神经保护和促进康复的新方法
  • 批准号:
    10584833
  • 财政年份:
    2022
  • 资助金额:
    $ 33.69万
  • 项目类别:
Targeting circulating endothelial glycocalyx fragments to reduce septic encephalopathy
靶向循环内皮糖萼片段以减少脓毒性脑病
  • 批准号:
    9922971
  • 财政年份:
    2017
  • 资助金额:
    $ 33.69万
  • 项目类别:
Targeting TRPM2 channels to improve synaptic and cognitive function after cerebral ischemia
靶向TRPM2通道改善脑缺血后的突触和认知功能
  • 批准号:
    9203070
  • 财政年份:
    2016
  • 资助金额:
    $ 33.69万
  • 项目类别:
Bead-Based Approach for Combined Mechanical and Pharmacological Treatment of Acut
基于珠子的急性急性机械和药物联合治疗方法
  • 批准号:
    8742017
  • 财政年份:
    2013
  • 资助金额:
    $ 33.69万
  • 项目类别:
Bead-Based Approach for Combined Mechanical and Pharmacological Treatment of Acut
基于珠子的急性急性机械和药物联合治疗方法
  • 批准号:
    8637561
  • 财政年份:
    2013
  • 资助金额:
    $ 33.69万
  • 项目类别:
GABA-A Receptor Rescue as a Neuroprotective Strategy in Cerebral Ischemia
GABA-A 受体拯救作为脑缺血的神经保护策略
  • 批准号:
    7370188
  • 财政年份:
    2007
  • 资助金额:
    $ 33.69万
  • 项目类别:
GABA-A Receptor Rescue as a Neuroprotective Strategy in Cerebral Ischemia
GABA-A 受体拯救作为脑缺血的神经保护策略
  • 批准号:
    7616219
  • 财政年份:
    2007
  • 资助金额:
    $ 33.69万
  • 项目类别:
GABA-A Receptor Rescue as a Neuroprotective Strategy in Cerebral Ischemia
GABA-A 受体拯救作为脑缺血的神经保护策略
  • 批准号:
    8103597
  • 财政年份:
    2007
  • 资助金额:
    $ 33.69万
  • 项目类别:
GABA-A Receptor Rescue as a Neuroprotective Strategy in Cerebral Ischemia
GABA-A 受体拯救作为脑缺血的神经保护策略
  • 批准号:
    7846096
  • 财政年份:
    2007
  • 资助金额:
    $ 33.69万
  • 项目类别:

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