Dysfunction of Sodium Homeostasis in Migraine

点击翻译按钮获取中文摘要

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.