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) 在美国是一个日益严重的医学和社会问题，因为研究表明它会对多个大脑区域的多巴胺和血清素神经末梢产生长期的神经退行性损伤。这种神经毒性已被证明与 METH 介导的活性氧 (ROS) 的产生有关；据信，这些起始事件会导致氧化应激，进而导致个体出现精神病和暴力行为。氧气 (O2) 既是 ROS 的来源，也是许多对大脑功能很重要的酶的末端电子受体，包括那些参与神经递质多巴胺、血清素和去甲肾上腺素生物合成的酶，这些物质与冰毒滥用有关。因此，滥用冰毒导致的脑组织氧分压（pO2）的改变可能直接影响体内平衡并导致冰毒引起的神经毒性。最近，我们获得了有趣的初步结果，显示急性 METH 给药后，通过 EPR 血氧测定法，脑组织 pO2 局部急剧下降，表明迫切需要充分确定 METH 滥用后大脑中组织 pO2 变化可能的异质分布。这种组织 pO2 变化发生在中风和创伤性脑损伤后，并且已从 METH 诱导的神经毒性的体外研究中得到提示，但与体内 METH 相关的脑组织 pO2 测量尚未得到探索，部分原因是缺乏足够的分析方法。我们建议合成电子顺磁共振（EPR）O2敏感的同位素取代硝基氧，例如可以递送到并分布在整个大脑的自旋探针，其可以在小鼠接受METH后通过EPR成像（EPRI）来绘制和量化脑组织O2。在目标 1 中，我们将在小鼠大脑中合成用于 EPRI 的新型同位素取代的硝基氧血氧测定探针，并确定最有效的硝基氧以及成功使用这些探针作为 EPRI 试剂的最佳条件。在目标 2 中，我们将在小鼠模型中给予 METH 后通过 EPRI 获得脑组织 pO2 的时间和空间分布。我们提出的研究的成功执行将对我们绘制大脑中组织 pO2 的能力产生巨大影响，并了解脑组织 pO2 变化在冰毒滥用病理生理学中的机制意义，为冰毒引起的神经毒性领域提供新的见解。