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.

Public Health Relevance

Many people with migraine remain disabled, even with good diagnosis and treatment, and it is a mystery why migraine starts. We found sodium levels in the brain are a common initial pathway, and a sodium pump blocker protects the rat migraine model. We will test how this works compared to common migraine drugs, and will determine if low and safe doses of a common sodium modulator can protect this migraine model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS072497-06A1
Application #
9818829
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Oshinsky, Michael L
Project Start
2011-08-01
Project End
2024-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Huntington Medical Research Institutes
Department
Type
DUNS #
077978898
City
Pasadena
State
CA
Country
United States
Zip Code
91105
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