Exacerbation of Alzheimer's Disease by Nitrous Oxide

一氧化二氮会加剧阿尔茨海默病

基本信息

  • 批准号:
    6576030
  • 负责人:
  • 金额:
    $ 7.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-09-30 至 2005-08-31
  • 项目状态:
    已结题

项目摘要

Research Topic: 3. Alzheimer's Disease Drug Discovery. Recent clinical reports indicate that the onset of Alzheimer's disease (AD) is earlier with prior mild neurologic insults or with increasing prior anesthetic exposure. The specific characteristics of anesthesia history that predispose to this earlier onset of AD are unknown but such observations raise the concern that something about anesthesia may constitute a mild neurologic insult. NMDA antagonists such as nitrous oxide (N20) and MK801 have been demonstrated to have a bimodal dose-related protective and then neurotoxic effect in normal rodents, with congruent regional activation by N20 reported in humans. There is ample data indicating an important role for neuroexcitation with associated oxidative injury in the pathogenesis of AD. It thus becomes reasonable to suggest an interaction between the genesis of AD and prior N20 exposure. Clinically N20 is an extremely common anesthetic with virtually ubiquitousexposure by almost everyone at some point in life. This makes its use a reasonable and potentially immensely important area to explore in the pathogenesis of AD. We hypothesize that N20 exposure has a bimodal dose-related effect to either attenuate or exacerbate subsequently developed AD. We will test the specific hypotheses that: 1. High dose N20 exposure exacerbates cognitive dysfunction and brain damage with AD. In a transgenic model of AD, mice will receive five high-dose exposures to N20 during middle-aged, or elderly ages followed at age 10 months by cognitive assessment, analysis of brain isoprostanes as markers of peroxidation and soluble andinsoluble amyloid, and morphologic assessment for amyloid plaques, apoptosis and neuronal degeneration 2. Low dose repetitive N20 exposure attenuates cognitive dysfunction and brain damage with AD. In a transgenic model of AD, mice will receive low doses of N20 nightly from mid-life to elderly ages, followed at age 10 months by cognitive assessment, analysis of brain isoprostanes and soluble and insoluble amyloid, and morphologic assessment for amyloid plaques, apoptosis and neuronal degeneration. Anesthesia has been implicated in postoperative cognitive dysfunction (POCD) in the elderly and has been impugned in the early onset of AD. The proposed research will explore the potential contribution of a ubiquitous anesthetic with neuroexcitatory side effects in a relevant murine model of AD. This will contribute to a focussed evaluation of the potential causes of POCD the results of which will change the practice of anesthesia and thus significantly attenuate the incidence of POCD in the elderly and possibly impact on the epidemiology of AIzheimer's disease. Moreover, observation of a protective effect may result in discovery of an easily implemented preventative drug therapy for AD.
研究课题:3.阿尔茨海默病药物发现。最近的临床报告表明,阿尔茨海默氏病 (AD) 的发病时间较早,先前有轻度神经损伤或先前麻醉剂暴露增加。导致 AD 早期发作的麻醉史的具体特征尚不清楚,但此类观察结果引起了人们的关注,即麻醉方面的某些因素可能构成轻微的神经损伤。 NMDA 拮抗剂如一氧化二氮 (N20) 和 MK801 已被证明对正常啮齿动物具有双峰剂量相关的保护作用和神经毒性作用,在人类中报道 N20 具有一致的区域激活作用。 有大量数据表明神经兴奋和相关氧化损伤在 AD 发病机制中发挥着重要作用。因此,AD 的发生与之前接触 N20 之间存在相互作用的说法是合理的。临床上,N20 是一种极其常见的麻醉剂,几乎每个人在生命中的某个阶段都会接触到它。这使得它的使用成为探索 AD 发病机制的合理且潜在极其重要的领域。 我们假设 N20 暴露具有双峰剂量相关效应,可以减轻或加剧随后发生的 AD。我们将测试以下具体假设: 1. 高剂量 N20 暴露会加剧 AD 引起的认知功能障碍和脑损伤。在 AD 转基因模型中,小鼠将在中年或老年期间接受 5 次高剂量 N20 暴露,然后在 10 个月大时进行认知评估,分析大脑异前列烷作为过氧化和可溶性和不溶性淀粉样蛋白的标记物,并对淀粉样斑块、细胞凋亡和神经元变性进行形态学评估 2. 低剂量重复 N20 暴露可减轻 AD 引起的认知功能障碍和脑损伤。在 AD 转基因模型中,小鼠从中年到老年每晚接受低剂量的 N20,然后在 10 个月大时进行认知评估、脑异前列烷和可溶性和不溶性淀粉样蛋白分析,以及淀粉样斑块、细胞凋亡和神经元变性的形态学评估。 麻醉与老年人术后认知功能障碍 (POCD) 有关,并且在 AD 早期发病中也受到质疑。拟议的研究将探索具有神经兴奋副作用的普遍麻醉剂在 AD 相关小鼠模型中的潜在贡献。这将有助于对 POCD 的潜在原因,其结果将改变麻醉实践,从而显着降低老年人 POCD 的发病率,并可能影响艾茨海默病的流行病学。此外,对保护作用的观察可能会发现一种易于实施的 AD 预防药物疗法。

项目成果

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W ANDREW KOFKE其他文献

W ANDREW KOFKE的其他文献

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{{ truncateString('W ANDREW KOFKE', 18)}}的其他基金

Prescribed opioid induced brain damage in chronic pain patients
处方阿片类药物引起慢性疼痛患者脑损伤
  • 批准号:
    10473879
  • 财政年份:
    2021
  • 资助金额:
    $ 7.93万
  • 项目类别:
Detection of Cerebral Ischemia With a Noninvasive Neurometabolic Optical Monitor
使用无创神经代谢光学监测仪检测脑缺血
  • 批准号:
    9222821
  • 财政年份:
    2014
  • 资助金额:
    $ 7.93万
  • 项目类别:
Detection of Cerebral Ischemia With a Noninvasive Neurometabolic Optical Monitor
使用无创神经代谢光学监测仪检测脑缺血
  • 批准号:
    9021009
  • 财政年份:
    2014
  • 资助金额:
    $ 7.93万
  • 项目类别:
Detection of Cerebral Ischemia With a Noninvasive Neurometabolic Optical Monitor
使用无创神经代谢光学监测仪检测脑缺血
  • 批准号:
    8696339
  • 财政年份:
    2014
  • 资助金额:
    $ 7.93万
  • 项目类别:
Detection of Cerebral Ischemia With a Noninvasive Neurometabolic Optical Monitor
使用无创神经代谢光学监测仪检测脑缺血
  • 批准号:
    9438563
  • 财政年份:
    2014
  • 资助金额:
    $ 7.93万
  • 项目类别:
Validation of NIRS CBF with XeCTCBF
使用 XeCTCBF 验证 NIRS CBF
  • 批准号:
    8036098
  • 财政年份:
    2010
  • 资助金额:
    $ 7.93万
  • 项目类别:
Genes in Human Brain Ischemia
人脑缺血的基因
  • 批准号:
    8139019
  • 财政年份:
    2010
  • 资助金额:
    $ 7.93万
  • 项目类别:
Validation of NIRS CBF with XeCTCBF
使用 XeCTCBF 验证 NIRS CBF
  • 批准号:
    7893486
  • 财政年份:
    2010
  • 资助金额:
    $ 7.93万
  • 项目类别:
Genes in Human Brain Ischemia
人脑缺血的基因
  • 批准号:
    8048271
  • 财政年份:
    2010
  • 资助金额:
    $ 7.93万
  • 项目类别:

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