Methamphetamine, Stress and Brain Endothelium

描述（由申请人提供）：甲基苯丙胺（冰毒）的滥用及其对脑神经递质系统的毒性是众所周知的，但其对其他目标（如脑微血管内皮）的潜在损害却被忽视了。此外，由于甲基苯丙胺与压力和创伤后应激障碍等其他健康问题高度共病，因此了解压力和甲基苯丙胺之间的机制基础至关重要，这样才能制定有效的治疗策略，有效地治疗甲基苯丙胺滥用和过量的范围。该建议研究了与压力和冰毒滥用共同发病相关的一个新后果，该后果被证明是对血脑屏障（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有关的综合影响，并评估滥用冰毒造成的压力诱发的脑损伤加剧对人类健康造成的风险。我们的工作模型为以下假设提供了基础：慢性应激性神经炎症是甲基苯丙胺暴露后观察到的血脑屏障损伤的一个促成因素，这种损伤表现为大分子外渗到脑实质和内皮紧密连接蛋白磷酸化依赖性减少。翻译的基本原理是开发一种新颖可行的神经保护策略，以神经炎症为目标，既可以预防，也可以拯救血脑屏障免受压力和冰毒联合暴露的有害后果。三个不同但互补的目标将解决我们的假设。特异性目标1将确定连续暴露于慢性应激和自我服用甲基苯丙胺后血脑屏障通透性的持续时间和程度。特异性目标2将检查血脑屏障通透性的潜在原因，并阐明通透性改变的时间依赖性神经炎症机制。具体目标3将通过检查与“冰毒口”相关的口腔细菌（牙龈假单品）进入大脑所引起的神经炎症的增加，确定连续暴露于压力和冰毒所产生的血脑屏障通透性增加的后果。研究结果将产生总体积极的影响，因为确定血脑屏障破裂的原因和后果可以指导设计未来治疗甲基苯丙胺神经毒性和过量的治疗策略。希望从根本上推进药物滥用引起的脑损伤领域，通过扩大甲基苯丙胺毒性的重要性，包括对脑血管内皮的长期影响，从而开始理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.