Regulation of cerebrospinal fluid and brain tissue sodium levels by choroid plexus and brain capillary endothelial cell Na+, K+-ATPases during migraine

Abstract

Background It is known that sodium concentration in both cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) increases during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Methods Under the hypothesis that disturbed homeostasis of brain capillary endothelial cells (CEC) and choroid plexus (CP) Na+, K+-ATPase (NKAT) is the underlying cause of the elevated CSF and ISF sodium levels in migraine sufferers, we developed a mechanistic, differential equation model of a rat’s brain to compare the significance of CP and CEC NKATs in controlling CSF and ISF sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue, plasma and CP. The activity levels of CP and CEC NKATs are modeled by permeability coefficients of CP and CEC to sodium, respectively. We then performed a global sensitivity analysis to investigate the significance of CEC and CP permeabilities to sodium in controlling CSF and ISF sodium concentrations. Results We show that the variation of permeability of CP to sodium is much more important than the alteration of CEC permeability to sodium in controlling CSF and ISF sodium levels. Our simulations indicate that the sodium flux at the interface of the ventricular system and brain tissue is greater than the sodium flux at the contact surface of the brain tissue and subarachnoid space during an episode of migraine. Conclusions Using mathematical modeling, we demonstrate that overactivity of CP NKATs has a more significant effect than overactivity of CEC NKATs on ISF and CSF sodium concentrations. Our results suggest that altered homeostasis of CP NKATs is a potential cause of migraines in the rats. Further studies on CP NKAT activity levels during migraine episodes with different triggers can help better understand migraine pathophysiology.