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.

项目概要/摘要 血脑屏障 (BBB) 包括中枢神经系统和大脑之间的物理和酶界面 中枢神经系统和脉管系统之间的通讯是通过什么来介导的。 称为神经血管单元（NVU），是一种具有先兆的高度动态结构，是一个多相的、 影响 3200 万美国人（占美国成年人的 14.2%）的神经系统疾病，估计每年花费 在美国花费了 170 亿美元，其特点是极度疼痛和皮质功能障碍（即 皮质扩散抑制（CSD）。CSD 和疼痛都会削弱 BBB 的完整性。 理解调节偏头痛引起的 BBB 改变的生物机制对于 了解抗偏头痛药物在偏头痛期间的功效。响应 PA-14-068（神经生物学）。 偏头痛），研究 BBB 通透性的变化（即血液到中枢神经系统摄取大脑不通透） 化合物）和紧密连接成分（即occludin、claudins等）将能够改善 了解 BBB 在发作性偏头痛中的作用。 CSD 可能会改变抗偏头痛疗法（包括一线疗法）的镇痛功效或中枢神经系统毒性 阐明这些偏头痛特征（即疼痛、CSD）如何影响功能。 药物转运蛋白（即有机阴离子转运多肽 (OATP) 和 Na+-H+ 交换蛋白）的表达 （NHE））可能会揭示偏头痛不同阶段（前驱期、 头痛和病后阶段）并导致确定新的治疗策略来治疗 完成这些研究将增进我们对发作性偏头痛期间血脑屏障完整性的理解。 并确定中枢神经系统在发作期间如何调节抗偏头痛治疗药物的吸收。 强烈表明 BBB 完整性会随着偏头痛的进展而动态受损， 反过来，改变抗偏头痛药物血液对中枢神经系统的吸收，我们证明了硬脑膜针刺±皮质。 KCl 在自由活动、非麻醉的雌性大鼠中：1) 诱导 CSD，2) 诱导持久的眼眶周围 此外，我们有证据支持 BBB 完整性在之后发生变化。 硬脑膜针刺 ± KCl 包括：3) 增强全脑对 14C-蔗糖、埃文斯蓝蛋白和 3H- 的摄取 舒马曲坦；4) 增加 OATP1A4 的蛋白表达，OATP1A4 是一种与中枢神经系统摄取有关的转运蛋白 多种药物治疗；5) 与相比，NHE1 蛋白（一种质子交换剂）水平降低 这些初步发现导致我们的假设： BBB 完整性失调是由偏头痛的不同阶段引起的，增加了偏头痛的严重程度和 头痛持续时间，同时调节抗偏头痛药物血液至中枢神经系统的摄取以减轻头痛 这笔赠款的目的将结合电生理学和行为学进行研究。 我们的实验室建立并使用了测量、原位灌注和分子技术。 目标 1 特别提出研究以确定 BBB 完整性，包括渗透性和分子 偏头痛的三个阶段（前驱期、头痛期和后遗症期）的组成，而目标 2 研究将阐明偏头痛期间中枢神经系统对抗偏头痛药物的吸收。 我们对阵发性偏头痛期间 BBB 完整性和中枢神经系统吸收的知识存在重大差距 抗偏头痛疗法有助于治疗偏头痛患者。