Exacerbation of Alzheimer's Disease by Nitrous Oxide

研究主题：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）的发病是早期与先前的轻度神经损伤或增加先前的麻醉剂暴露。麻醉史的具体特征，易患这种早期发作的AD是未知的，但这样的观察提出了关注，一些关于麻醉可能构成一个轻微的神经损伤。NMDA拮抗剂，如一氧化二氮（N20）和MK 801已被证明具有双峰剂量相关的保护，然后在正常啮齿动物神经毒性作用，与一致的区域激活N20报告在人类。 有大量的数据表明，神经兴奋与相关的氧化损伤在AD的发病机制中的重要作用。因此，提出AD的发生与先前的N20暴露之间的相互作用变得合理。临床上，N20是一种非常常见的麻醉剂，几乎每个人在生活中的某个时刻都暴露在几乎无处不在的环境中。这使得它的使用是一个合理的和潜在的非常重要的领域，探索在AD的发病机制。 我们假设N20暴露具有双峰剂量相关效应，以减轻或加重随后发展的AD。我们将检验以下具体假设： 1.高剂量N20暴露加重AD患者的认知功能障碍和脑损伤。在AD的转基因模型中，小鼠将在中年或老年期间接受5次高剂量的N20暴露，随后在10个月大时通过认知评估、作为过氧化和可溶性和不溶性淀粉样蛋白的标志物的脑异前列腺素的分析以及淀粉样蛋白斑块、细胞凋亡和神经元变性的形态评估 2.低剂量重复N20暴露减轻AD的认知功能障碍和脑损伤在AD的转基因模型中，小鼠将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，分析脑异前列腺素和可溶性和不溶性淀粉样蛋白，并对淀粉样蛋白斑块、细胞凋亡和神经元变性进行形态学评估。 麻醉与老年人术后认知功能障碍（POCD）有关，并在AD的早期发作中受到质疑。拟议的研究将探讨一种普遍存在的麻醉剂与神经兴奋性副作用在相关的AD小鼠模型的潜在贡献。这将有助于集中评价 POCD的潜在原因，其结果将改变麻醉的实践，从而显著降低老年人POCD的发病率，并可能影响阿尔茨海默病的流行病学。此外，观察到的保护作用可能会导致发现一种容易实施的预防性药物治疗AD。

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.