Methamphetamine-induced alterations in brain tissue oxygenation

描述（由申请人提供）：在美国，滥用甲基苯丙胺（METH）是一个日益严重的医学和社会问题，因为研究表明它会对大脑多个区域的多巴胺和血清素神经末端产生长期的神经退行性损伤。这种神经毒性已被证明与甲基苯丙胺介导的活性氧（ROS）的产生有关；据信，这些初始事件导致氧化应激，随后在个体中产生精神病和暴力行为。氧（O2）既是活性氧的来源，也是许多酶的终端电子受体，这些酶对脑功能很重要，包括那些参与神经递质多巴胺、血清素和去甲肾上腺素的生物合成的酶，这些递质与冰毒滥用有关。因此，滥用冰毒导致脑组织氧分压（pO2）的改变可能直接影响体内平衡并导致冰毒诱导的神经毒性。最近，我们获得了有趣的初步结果，显示急性冰毒给药后EPR血氧仪显示局部脑组织pO2急剧下降，这表明迫切需要充分确定冰毒滥用后脑组织pO2改变的可能异质性分布。这种组织pO2变化发生在中风和创伤性脑损伤之后，并且已经从甲基安非他明诱导的神经毒性的体外研究中提出，但脑组织pO2测量与体内甲基安非他明相关尚未进行探索，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）对O2敏感的同位素取代氮氧化物，例如，可以递送和分布于整个大脑的自旋探针，它可以在小鼠接受冰毒后通过EPR成像（EPRI）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新的基于同位素取代氮氧化物的EPRI氧饱和度测定探针，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。在目的2中，我们将在小鼠模型中通过EPRI获得甲基安非他明给药后脑组织pO2的时空分布。本研究的成功实施将对我们绘制脑组织pO2的能力产生巨大影响，并了解脑组织pO2变化在甲基安非他明滥用病理生理中的机制意义，为甲基安非他明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.