# Dysfunction of Sodium Homeostasis in Migraine

> **NIH NIH R01** · HUNTINGTON MEDICAL RESEARCH INSTITUTES · 2023 · $596,921

## Abstract

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.

## Key facts

- **NIH application ID:** 10685297
- **Project number:** 5R01NS072497-10
- **Recipient organization:** HUNTINGTON MEDICAL RESEARCH INSTITUTES
- **Principal Investigator:** Xianghong Arakaki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $596,921
- **Award type:** 5
- **Project period:** 2011-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685297

## Citation

> US National Institutes of Health, RePORTER application 10685297, Dysfunction of Sodium Homeostasis in Migraine (5R01NS072497-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10685297. Licensed CC0.

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