Blood Brain Barrier and Migraine: Effect on Therapy

血脑屏障和偏头痛：对治疗的影响

• 批准号: 10199058
• 负责人: Tally Marie Milnes
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-29 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199058
• 关键词: Absence of pain sensation; Address; Adult; Affect; Albumins; American; Analgesics; Applications Grants; Behavior; Behavioral; Biological; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Calcitonin Gene-Related Peptide; Cephalic; Characteristics; Classic Migraine; Clinical; Clinical Trials; Communication; Comprehension; Data; Development; Disease; Drug Delivery Systems; Electrophysiology (science); Estrogens; Evans blue stain; Event; Expenditure; Fatigue; Female; Functional disorder; Future; Grant; Head; Headache; Headache Disorders; Health Care Costs; Hour; In Situ; Inflammation; Inhalation Anesthetics; Injections; Institute of Medicine (U.S.); Investigation; Kinetics; Knowledge; Laboratories; Lead; Mediating; Mental Depression; Methods; Migraine; Molecular; NHE1; Nausea and Vomiting; Neurobiology; Neurologic Symptoms; Non-Steroidal Anti-Inflammatory Agents; OATP Transporters; Pain; Pain intensity; Patients; Peptides; Perfusion; Peripheral; Permeability; Pharmaceutical Preparations; Phase; Population; Pre-Clinical Model; Proteins; Protons; Rat-1; Rattus; Recurrence; Reporting; Role; Severities; Smell Perception; Spreading Cortical Depression; Stroke; Structure; Sucrose; Sumatriptan; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; Time; Toxic effect; Traction; Treatment Efficacy; United States; allodynia; awake; base; behavior measurement; blood-brain barrier disruption; blood-brain barrier permeabilization; chronic pain; claudin 3; cost; experience; improved; nervous system disorder; neurovascular unit; novel strategies; novel therapeutic intervention; occludin; pre-clinical; preclinical study; protein expression; response; sound; spreading depression; statistics; targeted agent; triptans; uptake

Project Summary/Abstract The Blood-Brain Barrier (BBB) comprises a physical and enzymatic interface between the CNS and the peripheral circulation. Communication between the CNS and vasculature is mediated through what has been termed the neurovascular unit (NVU), a highly dynamic structure. Migraine with aura is a multiphase, neurological disorder that affects 32 million Americans (14.2% of US adults), with an estimated annual cost of 17 billion dollars in the United States, that is characterized by excruciating pain and cortical dysfunction (i.e. cortical spreading depression, CSD). Both CSD and pain weaken the integrity of the BBB. A clear comprehension of biological mechanisms regulating migraine-induced alterations of the BBB is vital to understand the efficacy of antimigraine drugs during migraine. In response to PA-14-068 (Neurobiology of Migraine), investigating changes in BBB permeability (i.e. blood to CNS uptake of brain impermeant compounds) and tight junction composition (i.e., occludin, claudins, etc.) will enable an improved understanding of the role of the BBB in the development of episodic migraine. Disruption of the BBB by pain and CSD may alter analgesic efficacy or CNS toxicity of anti-migraine therapeutics, including first-line therapies like triptan compounds. Elucidating how these migraine features (i.e., pain, CSD) contribute to the functional expression of drug transporters (i.e., organic anion transporting polypeptides (OATPs) and Na+-H+ exchangers (NHEs)) may uncover mechanisms required for triptan analgesia at varying stages of migraine (prodromal, headache and postdrome phases) and lead to the identification of novel therapeutic strategies to treat migraine. Completion of these studies will advance our understanding of BBB integrity during episodic migraine and determine how CNS uptake of antimigraine therapeutics is regulated during attacks. Our preliminary data strongly suggest that the BBB integrity is dynamically compromised with migraine progression which, in turn, alters antimigraine medication blood to CNS uptake. We demonstrate that dural pinprick ± cortical KCl in freely moving, non-anesthetized female rats: 1) induces CSD and 2) induces long-lasting periorbital allodynia and head-tucking behavior. Moreover, we show evidence supporting that BBB integrity changes after dural pinprick ± KCl including: 3) enhanced whole brain uptake of 14C-sucrose, Evans’ Blue Albumin and 3H- sumatriptan; 4) increased protein expression of OATP1A4, a transporter implicated in CNS uptake of numerous medications; and 5) decreased levels of NHE1 protein, a proton exchanger, as compared to controls; these may alter sumatriptan uptake kinetics. These preliminary findings led to our hypothesis that dysregulation of BBB integrity is driven by the different migraine phases increasing the severity and duration of headache while regulating anti-migraine medication blood-to-CNS uptake to mitigate the disorder. The aims of this grant will be investigated using a combination of electrophysiological, behavioral measurements, in situ perfusion, and molecular techniques established and working in our laboratories. Specifically Aim 1 proposes studies to determine the BBB integrity, including permeability and molecular composition, during the three phases of migraine (prodromal, headache and postdrome phases), while Aim 2 studies will elucidate the CNS uptake of antimigraine agents during migraine. Completed studies will address significant gaps in our knowledge regarding BBB integrity during episodic migraine and CNS uptake of antimigraine therapeutics to aid in the treatment of patients suffering from migraine.

项目摘要/摘要 血脑屏障（BBB）包括CNS和 外围循环。中枢神经系统与脉管系统之间的沟通是通过过去的 称为神经血管单元（NVU），一种高度动态的结构。带有光环的偏头痛是多相， 影响3200万美国人（美国成年人的14.2％）的神经系统疾病，估计每年成本为 在美国，有170亿美元的特征是疼痛和皮质功能障碍（即 皮质扩散抑郁症，CSD）。 CSD和痛苦都弱化了BBB的完整性。清晰 理解调节偏头痛引起的BBB改变的生物学机制对于 了解偏头痛期间抗诊断药物的效率。响应PA-14-068（神经生物学 偏头痛），调查BBB渗透性的变化（即血液到中枢神经系统的吸收脑不足 化合物）和紧密连接组合物（即occludin，claudins等）将启用改进 了解BBB在情节性偏头痛发展中的作用。痛苦破坏BBB 和CSD可能会改变抗迁移疗法的镇痛效率或中枢神经系统的毒性，包括一线疗法 像triptan化合物。阐明这些偏头痛特征（即疼痛，CSD）如何有助于功能 药物转运蛋白的表达（即有机阴离子转运多肽（OATP）和Na+ -H+交换器 （nhes））可能会发现在偏头痛不同阶段的triptan镇痛所需的机制（Promamal， 头痛和验尸阶段），并导致鉴定出治疗的新型治疗策略 偏头痛。这些研究的完成将提高我们对情节偏头痛期间BBB完整性的理解 并确定在攻击期间如何调节CNS抗杂化疗法的摄取。我们的初步数据 强烈暗示BBB完整性被偏头痛的进展动态损害，这是 反过来，将抗诊断药物的血液变为中枢神经系统的吸收。我们证明了硬脑膜pinprick±皮质 KCL在自由移动的，非麻醉的雌性大鼠中：1）诱导CSD和2）诱导持久的周长 异常性和头部挑剔的行为。此外，我们显示了支持BBB完整性后变化的证据 硬脑膜针刺±kCl包括：3）增强了14c核，埃文斯的蓝色白蛋白和3H-的整个大脑吸收 sumatriptan; 4）增加了OATP1A4的蛋白质表达，这是一种在CNS摄取中实施的转运蛋白 许多药物； 5）与质子交换剂NHE1蛋白的水平相比 控件；这些可能会改变苏门普坦的摄取动力学。这些初步发现导致了我们的假设 BBB完整性的失调是由不同偏头痛阶段驱动的，从而增加了严重性和 标头的持续时间，同时调查抗毛因药物的血液到CNS摄取以减轻 紊乱。该赠款的目的将使用电生理，行为的组合进行研究 测量，原位灌注以及在我们的实验室中建立和工作的分子技术。 特别针对1个建议研究来确定BBB完整性，包括渗透性和分子 组成，在偏头痛的三个阶段（前驱，标题和后斑点阶段），而AIM 2 研究将阐明偏头痛期间抗焦点剂的中枢神经系统摄取。完成的研究将解决 在情节偏头痛和中枢神经系统吸收期间，我们有关BBB完整性的知识差距很大 反诊断治疗以帮助治疗患有偏头痛的患者。