Methamphetamine, Stress and Brain Endothelium

描述（由申请人提供）：甲基苯丙胺（Meth）的猖獗滥用及其对脑神经递质系统的毒性是众所周知的，但其对其他靶点（如脑微血管内皮）的潜在损害却被忽视了。此外，由于Meth与其他健康问题（如压力和创伤后应激障碍）高度共病，因此必须了解压力和Meth之间的机制基础，以便制定有效的治疗策略，以有效地治疗Meth滥用和过量的范围。 该提案审查了与压力和甲基苯丙胺滥用共病相关的新后果，其证据是对血脑屏障（BBB）和脑微血管内皮的长期损害。长期目标是确定与这种合并症相关的综合影响，并评估滥用甲代安引起的压力诱发脑损伤加重对人类健康产生的风险。我们的工作模型为以下假设提供了基础：慢性应激诱导的神经炎症是Meth暴露后观察到的BBB损伤的促成因素，并且这种损伤表现为大分子外渗到脑实质中和内皮紧密连接蛋白的磷酸化依赖性降低。翻译的基本原理是开发一种新的和可行的神经保护策略，其靶向神经炎症，并且是预防性的或可以将BBB从由压力和甲基组合暴露引起的有害后果中拯救出来。 三个不同但互补的目标将解决我们的假设。具体目标1将确定在连续暴露于慢性应激和自我施用甲氧苄氨蝶呤后BBB渗透性的持续时间和程度。具体目标2将检查血脑屏障通透性的根本原因，并将阐明负责通透性变化的时间依赖性神经炎症机制。具体目标3将通过检查由与“甲基口腔”相关的口腔细菌牙龈卟啉单胞菌进入脑引起的神经炎症的增强来确定由连续暴露于应激和甲基所产生的BBB的渗透性增加的后果。这些发现将产生总体积极的影响，因为确定BBB破坏的原因和后果可以指导未来治疗METH神经毒性和过量的治疗策略的设计。希望从根本上推进药物滥用诱导的脑损伤领域，通过扩大甲基毒性的意义，包括对脑血管内皮的长期影响，从而开始了解与这种影响相关的深远的神经生物学后果。

DESCRIPTION (provided by applicant): The rampant abuse of methamphetamine (Meth) and its documented toxicity to brain neurotransmitter systems are well known but its potential damage to other targets such as the brain microvascular endothelium has been overlooked. Moreover, because Meth is highly co-morbid with other health concerns such as stress and post-traumatic stress disorder, it is imperative that the mechanistic underpinnings between stress and Meth are understood so that effective therapeutic strategies can be developed to effectively treat the scope of Meth abuse and overdose. The proposal examines a new consequence associated with the co-morbidity of stress and Meth abuse that is evidenced by long-term damage to the blood-brain barrier (BBB) and brain microvascular endothelium. The long term goal is to identify the comprehensive effects associated with this co-morbidity and assess the risk to human health produced by stress-induced augmentation of brain injury resulting from the abuse of Meth. Our working model provides the basis for the hypothesis that chronic stress-induced neuroinflammation is a contributory factor to the BBB damage observed after Meth exposure and that this damage is manifested as large molecule extravasation into the brain parenchyma and phosphorylation-dependent decreases in endothelial tight junction proteins. The translational rationale is to develop a novel and feasible neuroprotective strategy that targets neuroinflammation and is either prophylactic or can rescue the BBB from the harmful consequences resulting from the combined exposures to stress and Meth. Three distinct but complementary aims will address our hypothesis. Specific Aim 1 will identify the duration and degree of BBB permeability after the serial exposure to chronic stress and the self administration of Meth. Specific Aim 2 will examine the underlying causes of BBB permeability and will elucidate the time-dependent neuroinflammatory mechanisms responsible for the permeability changes. Specific Aim 3 will determine the consequences of the increased permeability of the BBB produced by the serial exposure to stress and Meth by examining the augmentation of neuroinflammation caused by entrance of the oral bacterium associated with "Meth mouth", p. gingivalis, into the brain. The findings will have an overall positive impact because the determination of the causes and consequences of a breach in the BBB can guide the design of future therapeutic strategies for the treatment of METH neurotoxicity and overdose. The hope is to fundamentally advance the field of drug abuse-induced brain injury in general, by broadening the significance of Meth toxicity to include the long-term impact on the cerebral vasculature endothelium and thereby begin to understand the far reaching neurobiological consequences associated with this effect.