Dysfunction of Sodium Homeostasis in Migraine

偏头痛中的钠稳态功能障碍

• 批准号: 10685297
• 负责人: Xianghong Arakaki
• 金额: $ 59.69万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685297
• 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; Fluid Balance; 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; Symptoms; Testing; Thalamic structure; Theoretical model; Time; Trigeminal System; Vascular Cell Adhesion Molecule-1; Ventricular; Water; Work; allodynia; antagonist; brain tissue; cerebrospinal fluid flow; comorbidity; experimental study; extracellular; improved; in vivo; insight; neuron component; neuronal excitability; phospholemman; preclinical study; predictive modeling; prevent; protein biomarkers; quantum; regional difference; response; simulation; 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“残疾生活年限”的五大主要原因之一。即使是好的

项目成果

Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine.

• DOI: 10.3389/fnmol.2021.691733
• 发表时间: 2021
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Castor K;Dawlaty J;Arakaki X;Gross N;Woldeamanuel YW;Harrington MG;Cowan RP;Fonteh AN
• 通讯作者: Fonteh AN