Methamphetamine, Stress and Brain Endothelium

甲基苯丙胺、压力和脑内皮细胞

• 批准号: 9044745
• 负责人: Bryan K Yamamoto
• 金额: $ 44.7万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044745
• 关键词: Acute; Address; Bacteria; Bacterial Infections; Benchmarking; Biological; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Injuries; Cerebrovascular system; Chronic stress; Comorbidity; Diffusion; Dinoprostone; Disease; Dose; Drug Exposure; Drug abuse; Elements; Endothelium; Event; Exposure to; Extravasation; Future; Goals; Health; Human; Hyperthermia; Infiltration; Inflammation; Inflammatory; International; Measures; Mediating; Methamphetamine; Mission; Modeling; Neurobiology; Neurologic; Neurotransmitters; Oral; Oral cavity; Overdose; Permeability; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Porphyromonas gingivalis; Post-Traumatic Stress Disorders; Prostaglandin-Endoperoxide Synthase; Proteins; Public Health; Rattus; Regimen; Rho-associated kinase; Risk; Role; Seizures; Self Administration; Self-Administered; Signal Transduction; Stress; Stroke; Structure; System; Testing; Therapeutic; Tight Junctions; Time; Toxic effect; Toxin; Traumatic Brain Injury; Work; base; brain parenchyma; capillary; cerebral microvasculature; design; fluorescein isothiocyanate dextran; innovation; methamphetamine abuse; methamphetamine effect; methamphetamine exposure; neuroinflammation; neurotoxic; neurotoxicity; novel; oral bacteria; prophylactic; prostanoid receptor EP1; relating to nervous system; success; treatment strategy

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.

描述（由申请人提供）：甲基苯丙胺 (Meth) 的猖獗滥用及其对大脑神经递质系统的毒性众所周知，但其对大脑微血管内皮等其他目标的潜在损害却被忽视了。此外，由于冰毒与压力和创伤后应激障碍等其他健康问题高度共存，因此必须了解压力和冰毒之间的机制基础，以便制定有效的治疗策略，以有效治疗冰毒滥用和过量的范围。 该提案研究了与压力和冰毒滥用并存相关的新后果，血脑屏障（BBB）和脑微血管内皮的长期损伤证明了这一点。长期目标是确定与这种共病相关的综合影响，并评估因滥用冰毒而导致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：慢性应激诱导的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，并且这种损伤表现为大分子外渗到脑实质中以及内皮紧密连接蛋白的磷酸化依赖性减少。转化的基本原理是开发一种新颖且可行的神经保护策略，该策略针对神经炎症，并且可以预防或挽救 BBB 免受压力和冰毒联合暴露所造成的有害后果。 三个不同但互补的目标将解决我们的假设。具体目标 1 将确定连续暴露于慢性应激和自我服用冰毒后血脑屏障通透性的持续时间和程度。具体目标 2 将检查 BBB 通透性的根本原因，并阐明导致通透性变化的时间依赖性神经炎症机制。具体目标 3 将通过检查与“冰毒口”相关的口腔细菌进入引起的神经炎症的增强，确定连续暴露于压力和冰毒所产生的 BBB 通透性增加的后果，第 14 页。牙龈，进入大脑。这些发现将产生总体积极影响，因为确定血脑屏障破裂的原因和后果可以指导未来治疗冰毒神经毒性和药物过量的治疗策略的设计。希望通过扩大冰毒毒性的重要性，将其对脑血管内皮的长期影响纳入其中，从根本上推进药物滥用引起的脑损伤领域的研究，从而开始了解与这种效应相关的深远的神经生物学后果。