Blood Brain Barrier and Migraine: Effect on Therapy

项目摘要/摘要 血脑屏障(BBB)由中枢神经系统和脑组织之间的物理界面和酶界面组成 外周循环。中枢神经系统和血管系统之间的通信是通过已经被 被称为神经血管单位(NVU)，这是一种高度动态的结构。有先兆的偏头痛是一个多阶段的， 影响3200万美国人(14.2%的美国成年人)的神经障碍，估计每年的损失为 170亿美元，其特征是极度疼痛和皮质功能障碍(即 皮质扩散性抑制(CSD)。CSD和疼痛都削弱了血脑屏障的完整性。一目了然 理解调节偏头痛引起的血脑屏障改变的生物学机制对于 了解偏头痛期间抗偏头痛药物的疗效。对PA-14-068(神经生物学)的响应 偏头痛)，研究血脑屏障通透性的变化(即血液到中枢神经系统的脑内摄取 化合物)和紧密连接组成(即，阻滞素、克拉丁等)将实现改进的 了解血脑屏障在发作性偏头痛发生中的作用。疼痛引起的血脑屏障紊乱 CSD可能会改变包括一线治疗在内的抗偏头痛药物的止痛效果或中枢神经系统毒性 就像Triptan化合物。阐明这些偏头痛特征(即疼痛、CSD)如何对功能性 药物转运体(即有机阴离子转运多肽和Na+-H+交换体)的表达 (NHEs))可能揭示了偏头痛不同阶段曲普坦止痛所需的机制(前驱症状， 头痛和后遗症阶段)，并导致确定新的治疗策略 偏头痛。这些研究的完成将促进我们对偏头痛发作期血脑屏障完整性的理解 并确定在发作期间中枢神经系统对抗偏头痛治疗药物的摄取是如何调节的。我们的初步数据 强烈建议随着偏头痛的进展，血脑屏障的完整性会动态受损， 反过来，将抗偏头痛药物的血液改变为中枢神经系统的摄取。我们证明了硬脑膜针刺±皮质 自由活动、非麻醉雌性大鼠的KCL：1)诱导CSD；2)诱导持久的眶周 疼痛过敏症和缩头行为。此外，我们提供的证据支持血脑屏障完整性在以下方面的变化 硬脑膜针刺±氯化钾包括：3)促进全脑摄取~(14)C-蔗糖、伊文思蓝白蛋白和~3H- 舒马曲坦；4)OATP1A4的蛋白表达增加，OATP1A4是参与中枢神经系统摄取的转运蛋白。 多种药物；以及5)降低质子交换器NHE1蛋白的水平 对照；这些可能改变舒马曲坦的摄取动力学。这些初步发现导致了我们的假设 BBB完整性的失调是由偏头痛的不同阶段引起的， 调整抗偏头痛药物的血液到中枢神经系统的摄取以缓解头痛的持续时间 无序。这笔赠款的目的将使用电生理、行为学和 测量、原位灌流和分子技术已在我们的实验室建立和使用。 具体地说，目标1提出了确定血脑屏障完整性的研究，包括渗透性和分子 偏头痛三个阶段(前驱、头痛和后遗症)的成分，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摄取。已完成的研究将解决 我们对发作性偏头痛期间血脑屏障完整性和中枢神经系统摄取的认识存在显著差距 帮助治疗偏头痛患者的抗偏头痛疗法。

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.