Methamphetamine-induced alterations in brain tissue oxygenation

甲基苯丙胺引起的脑组织氧合变化

• 批准号: 8829813
• 负责人: Ke Jian Liu
• 金额: $ 18.74万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829813
• 关键词: Acute; Animals; Area; Attention; Blood - brain barrier anatomy; Brain; Brain imaging; Cerebrum; Chemicals; Chronic; Consumption; Corpus striatum structure; Detection; Development; Dopamine; Drug or chemical Tissue Distribution; Dyes; Electrodes; Electron Spin Resonance Spectroscopy; Enzymes; Event; Fluorescence; Frequencies; Functional disorder; Goals; Health; Homeostasis; Image; Imaging technology; In Situ; In Vitro; Individual; Ischemic Stroke; Lead; Life; Link; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediating; Medical; Methamphetamine; Methods; Modality; Molecular; Mus; Nerve; Nerve Degeneration; Norepinephrine; Oxidants; Oxidative Stress; Oxygen; Oxygen saturation measurement; Partial Pressure; Physiological; Pilot Projects; Preparation; Production; Rattus; Reactive Oxygen Species; Research; Resistance; Ruthenium; Series; Serotonin; Solutions; Source; Stroke; Temperature; Testing; Time; Tissues; Traumatic Brain Injury; Variant; Violence; base; biological systems; blood oxygen level dependent; brain tissue; design; flexibility; imaging agent; imaging modality; in vivo; insight; methamphetamine abuse; minimally invasive; mouse model; nervous system disorder; neurotoxicity; neurotransmitter biosynthesis; novel; pressure; temporal measurement; tissue oxygenation; vasoconstriction

DESCRIPTION (provided by applicant): Abuse of methamphetamine (METH) is a growing medical and societal problem in the US, as studies have suggested that it produces long-term neurodegenerative damage to dopamineric and serotonergic nerve terminals in multiple brain areas. This neurotoxicity has been shown to be associated with METH-mediated production of reactive oxygen species (ROS); it is believed that these initiating events result in oxidative stress with subsequent psychotic and violent behaviors in individuals. Oxygen (O2) is both the source of ROS and the terminal electron acceptor for many enzymes that are important in brain function, including those involved in the biosynthesis of the neurotransmitters dopamine, serotonin and norepinephrine that have been linked with METH abuse. Thus, alteration in cerebral tissue partial pressure of O2 (pO2) by METH abuse may directly impact homeostasis and lead to METH-induced neurotoxicity. Recently we have obtained intriguing preliminary results showing a localized dramatic decrease in cerebral tissue pO2 by EPR oximetry after acute METH administration, demonstrating the urgent need to fully define the possible heterogeneous distribution of tissue pO2 alterations in brain following METH abuse. Such tissue pO2 changes occur following stroke and traumatic brain injury and have been suggested from in vitro studies of METH-induced neurotoxicity, but cerebral tissue pO2 measurements associated with METH in vivo has not been explored, due in part, to a lack of adequate analytic methods. We propose to synthesize electron paramagnetic resonance (EPR) O2-sensitive isotopic-substituted nitroxides, e.g., spin probes that can be delivered to and distributed throughout the brain, which can map and quantify cerebral tissue O2 by EPR imaging (EPRI) after mice have received METH. In Aim 1, we will synthesize novel isotopic-substituted nitroxide-based oximetry probes for EPRI in a mouse brain and determine the most effective nitroxide in addition to the optimal conditions for the successful use of these probes as EPRI agents. In aim 2, we will obtain the temporal and spatial profile of cerebral tissue pO2 by EPRI following administration of METH in a mouse model. The successful execution of our proposed research will have tremendous impact on our ability to map tissue pO2 in the brain, and to understand the mechanistic significance of cerebral tissue pO2 variation in the pathophysiology of METH abuse providing new insights into the field of METH-induced neurotoxicity.

描述（由申请人提供）：滥用甲基苯丙胺（METH）是美国日益增长的医学和社会问题，因为研究表明，它在多个大脑区域对多巴胺和血清素能神经终末产生了长期神经退行性损害。该神经毒性已被证明与甲基介导的活性氧（ROS）的产生有关；人们认为，这些启动事件会导致氧化应激，随后在个体中的精神病和暴力行为。氧（O2）既是许多在脑功能中很重要的酶的ROS的来源，也是末端电子受体的来源，包括与滥用相关的神经递质多巴胺，5-羟色胺和去甲肾上腺素的生物合成的氧气。因此，通过滥用甲基甲基甲基甲基甲基O2（PO2）的脑组织部分压力的改变可能会直接影响稳态并导致甲基甲基化的神经毒性。最近，我们获得了有趣的初步结果，表明急性甲基苯甲酸酯后通过EPR血氧仪局部急剧减少局部急剧降低，这表明迫切需要完全定义甲基甲基苯丙胺滥用后脑中脑中组织PO2的可能异质分布。这种组织PO2发生在中风和脑损伤后发生，并且已经通过在甲基甲基菌引起的神经毒性的体外研究中提出，但是尚未探索与体内甲基甲基甲基苯酚相关的大脑组织PO2测量，部分原因是由于缺乏足够的分析方法。我们提议合成电子顺磁共振（EPR）O2敏感的同位素溶剂溶剂固定的氮氧化物，例如，可以通过EPR成像（EPRI）（EPRI）获得甲基甲基苯酚（EPR Imicting（EPRI）），可以将可以传递到整个大脑中并分布在整个大脑中。在AIM 1中，我们将合成新型的同位素基建造的基于硝基的氧化氧化探针，用于EPRI在小鼠脑中的EPRI，并确定除了成功将这些探针用作EPRI剂的最佳条件外，还确定了最有效的硝基氧化物。在AIM 2中，我们将通过EPRI在小鼠模型中给药后通过EPRI获得脑组织PO2的时间和空间谱。我们提出的研究的成功执行将对我们在大脑中绘制组织PO2的能力产生巨大影响，并了解脑组织PO2在METH滥用的病理生理学中的机理意义，从而为甲基苯丙胺诱导的神经毒性领域提供了新的见解。