Methamphetamine-induced alterations in brain tissue oxygenation

描述(申请人提供)：滥用甲基苯丙胺(冰毒)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5-羟色胺能神经末梢造成长期的神经变性损害。这种神经毒性已被证明与冰毒介导的活性氧自由基(ROS)的产生有关；人们认为这些启动事件会导致氧化应激，并导致个体随后的精神病和暴力行为。氧(O2)既是ROS的来源，也是许多酶的终端电子受体，这些酶对大脑功能非常重要，包括那些参与神经递质多巴胺、5-羟色胺和去甲肾上腺素的生物合成的酶，这些神经递质与冰毒滥用有关。因此，冰毒滥用引起的脑组织氧分压(PO2)的改变可能直接影响体内平衡，导致冰毒所致的神经毒性。最近，我们获得了有趣的初步结果，显示急性冰毒给药后EPR血氧测定仪显示脑组织PO2局部急剧下降，表明迫切需要充分确定冰毒滥用后脑组织PO2变化可能的异质性分布。这种组织氧分压变化发生在中风和创伤性脑损伤后，已经从冰毒诱导的神经毒性的体外研究中提出，但体内与冰毒相关的脑组织氧分压测量尚未被探索，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)氧敏感的同位素取代氮氧化物，例如，可以传递到大脑并分布在整个大脑中的自旋探针，它可以在小鼠接受冰毒后通过电子顺磁共振成像(EPRI)定位和定量脑组织氧。在目标1中，我们将为小鼠脑内的EPRI合成新的基于同位素取代氮氧化物的血氧测定探针，并确定最有效的氮氧化物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，我们将在小鼠模型上通过EPRI获得脑组织pO2的时间和空间分布。我们所提出的研究的成功实施将对我们在脑中定位组织PO2的能力产生巨大的影响，并了解脑组织PO2变化在冰毒病理生理学中的机制意义，为冰毒诱导的神经毒性领域提供新的见解。

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.