Dysfunction of Sodium Homeostasis in Migraine

偏头痛中的钠稳态功能障碍

• 批准号: 10452598
• 负责人: Xianghong Arakaki
• 金额: $ 60.92万
• 依托单位: HUNTINGTON MEDICAL RESEARCH INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452598
• 关键词: Albumins; Animals; Appearance; Biological Markers; Blood Vessels; Brain; Brain Stem; Calcitonin Gene-Related Peptide; Cardiology; Cell Adhesion; Cephalic; Cerebrospinal Fluid; Chemical Shift Imaging; Choroid Plexus Epithelium; Clinical Research; Common Migraine; Data; Diagnosis; Diagnostic; Digoxin; Disabled Persons; Disease; Dose; Drug Targeting; Exposure to; Eye; Failure; Fibrinogen; Functional disorder; Future; Homeostasis; Human; Hypersensitivity; K ATPase; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Measures; Metabolic; Migraine; Modeling; Moods; Na(+)-K(+)-Exchanging ATPase; Neurons; Nitroglycerin; Nociception; Outcome; Pain; Pathway interactions; Perfusion; Permeability; Persons; Pharmaceutical Preparations; Phosphorylation; Process; Protein Isoforms; Rattus; Reporting; Serotonin Agonists; Sodium; Source; Strabismus; Structure of choroid plexus; Sumatriptan; Testing; Thalamic structure; Theoretical model; Time; Trigeminal System; Vascular Cell Adhesion Molecule-1; Ventricular; Water; Work; allodynia; antagonist; brain tissue; cerebrospinal fluid flow; cohesion; comorbidity; experimental study; extracellular; improved; in vivo; insight; neuronal excitability; phospholemman; preclinical study; predictive modeling; prevent; protein biomarkers; quantum; regional difference; response; simulation; symptom treatment; theories; treatment choice; treatment response; triptans; vascular factor; years lived with disability

From 1990-2016, migraine was in the top 5 leading causes of “years lived with disability”. Even with good diagnosis and treatment (triptans, gepants, ditans, and glurants), many remain disabled. The prevailing trigeminovascular theory points to a combination of neuronal and vascular components, but the fundamental mechanism for why and when a migraine starts is still unclear. Our broad premise is that the varied triggers that initiate migraine, or medications that suppress it, act through a common pathway; finding this mechanism will offer a more cohesive strategy to treat migraine, complimentary to the empirical approach. We proposed a common pathway of altered cerebrospinal fluid (CSF) sodium concentration [Na+] in our recent RO1 NS072497 project: “Dysfunction of sodium homeostasis in a rat migraine model.” In this nitroglycerin (NTG) triggered model, we demonstrated [Na+] increased mainly in the ventricular CSF, using 23Na MRI. In humans, we found higher CSF [Na+] during migraine, which has been validated in an independent study of migraine, recently reported and also using 23Na MRI. To explore the relationship of increased [Na+] and hypersensitivity in migraine, we demonstrated that higher extracellular [Na+] increases neuronal excitability in simulations, in neural cells, and in vivo; that the effects can be mimicked by increasing [Na+] directly in the ventricles; and that NTG effects can be prevented by Na,K-ATPase inhibition targeted to the choroid plexus (CP) epithelium. These results suggest nociception arises from neurons exposed to higher extracellular [Na+] along the path of ventricular and subdural CSF. Our central hypothesis is that triggers of migraine alter CP Na,K-ATPase activity and CSF [Na+] homeostasis, which changes neuronal excitability and initiates migraine. Our hypothesis predicts that the most successful treatments will correct the altered Na,K-ATPase homeostasis. We will validate and examine the CP Na,K-ATPase activity and change in CSF [Na+] in the rat NTG model (Aim 1a), examine how the CP is altered (Aim 1b), and map how the CSF and brain tissue [Na+] change (Aims 1c & d). We will measure metabolic and trigemonovascular changes in brain tissue (Aim 1e) and examine how these features relate to CSF [Na+] and CP Na,K-ATPase activity. Aim 2 will test if typical migraine medications (sumatriptan and telcagepant) rescue the NTG-triggered nociception. These studies have the potential to support repurposing of digoxin at a low and safe dose (1/100 the dose currently used in cardiology) to inhibit the CP Na, K-ATPase and prevent surges in CSF [Na+]. These experiments will justify future efforts to optimize new modulators to regulate the CP Na,K-ATPase and CSF [Na+] biomarkers. The potential to improve brain homeostasis by adjusting CP and CSF [Na+] biomarkers may extend to other fluctuating disorders, such as migraine comorbid pain and mood conditions.

从1990年到2016年，偏头痛是“残疾年”的前5大主要原因。即使有良好 诊断和治疗（曲坦类、吉潘类、地坦类和glurants），许多人仍然残疾。现行 三叉神经血管理论指出了神经元和血管成分的组合，但 为什么以及何时开始偏头痛的基本机制仍然不清楚。我们的大前提是， 引发偏头痛的各种触发因素或抑制偏头痛的药物通过共同的途径起作用;发现 这种机制将提供一个更有凝聚力的策略来治疗偏头痛，补充经验， approach.我们提出了一个共同的途径改变脑脊液（CSF）钠浓度[Na+] 在我们最近的RO 1 NS 072497项目中：“大鼠偏头痛模型中钠稳态功能障碍”。在这 硝酸甘油（NTG）触发模型，我们证明[Na+]增加主要在脑室CSF中，使用 23Na MRI。在人类中，我们发现偏头痛期间CSF [Na+]较高，这已在一项研究中得到验证。 偏头痛的独立研究，最近报告，也使用23 Na MRI。为了探讨 偏头痛中[Na+]增加和超敏反应，我们证明了细胞外[Na+]增加， 神经元兴奋性在模拟，在神经细胞，并在体内;效果可以模仿 直接增加心室中的[Na+]; NTG效应可通过Na，K-ATP酶抑制来预防 靶向脉络丛（CP）上皮。这些结果表明，伤害性感受来自神经元 沿脑室和硬膜下CSF的路径暴露于较高的细胞外[Na+]沿着。我们的中央 假设偏头痛触发因素改变CP Na、K-ATP酶活性和CSF [Na+]稳态， 从而改变神经元的兴奋性并引发偏头痛。我们的假设预测， 成功的治疗将纠正改变的Na，K-ATP酶体内平衡。我们将验证和 检测NTG大鼠模型（Aim 1a）中CP Na，K-ATP酶活性和CSF [Na+]的变化， CP如何改变（目标1b），并绘制CSF和脑组织[Na+]如何变化（目标1c和d）。我们将 测量脑组织中的代谢和三叉神经血管变化（目标1 e），并检查这些变化是如何发生的。 特征与CSF [Na+]和CP Na，K-ATP酶活性有关。目标2将测试典型的偏头痛药物是否 （舒马曲坦和替卡吉潘）拯救NTG触发的伤害感受。这些研究有可能 支持重新利用低且安全剂量的地高辛（目前心脏病学使用剂量的1/100）来抑制 CP Na，K-ATP酶和防止CSF [Na+]激增。这些实验将证明今后的努力是正确的， 优化新的调节剂以调节CP Na，K-ATP酶和CSF [Na+]生物标志物。的潜力 通过调整CP和CSF [Na+]生物标志物改善脑内稳态可能扩展到其他波动的 例如偏头痛共病疼痛和情绪状况。