Research Article: Endogenous Na+, K+-ATPase inhibitors and CSF [Na+] contribute to migraine formation

Date Published: June 7, 2019

Publisher: Public Library of Science

Author(s): Noah B. Gross, Nastaren Abad, David Lichtstein, Shiri Taron, Lorena Aparicio, Alfred N. Fonteh, Xianghong Arakaki, Robert P. Cowan, Samuel C. Grant, Michael G. Harrington, Luis Eduardo M. Quintas.

http://doi.org/10.1371/journal.pone.0218041

Abstract

There is strong evidence that neuronal hyper-excitability underlies migraine, and may or may not be preceded by cortical spreading depression. However, the mechanisms for cortical spreading depression and/or migraine are not established. Previous studies reported that cerebrospinal fluid (CSF) [Na+] is higher during migraine, and that higher extracellular [Na+] leads to hyper-excitability. We raise the hypothesis that altered choroid plexus Na+, K+-ATPase activity can cause both migraine phenomena: inhibition raises CSF [K+] and initiates cortical spreading depression, while activation raises CSF [Na+] and causes migraine. In this study, we examined levels of specific Na+, K+-ATPase inhibitors, endogenous ouabain-like compounds (EOLC), in CSF from migraineurs and controls. CSF EOLC levels were significantly lower during ictal migraine (0.4 nM +/- 0.09) than from either controls (1.8 nM +/- 0.4) or interictal migraineurs (3.1 nM +/- 1.9). Blood plasma EOLC levels were higher in migraineurs than controls, but did not differ between ictal and interictal states. In a Sprague-Dawley rat model of nitroglycerin-triggered central sensitization, we changed the concentrations of EOLC and CSF sodium, and measured aversive mechanical threshold (von Frey hairs), trigeminal nucleus caudalis activation (cFos), and CSF [Na+] (ultra-high field 23Na MRI). Animals were sensitized by three independent treatments: intraperitoneal nitroglycerin, immunodepleting EOLC from cerebral ventricles, or cerebroventricular infusion of higher CSF [Na+]. Conversely, nitroglycerin-triggered sensitization was prevented by either vascular or cerebroventricular delivery of the specific Na+, K+-ATPase inhibitor, ouabain. These results affirm our hypothesis that higher CSF [Na+] is linked to human migraine and to a rodent migraine model, and demonstrate that EOLC regulates them both. Our data suggest that altered choroid plexus Na+, K+-ATPase activity is a common source of these changes, and may be the initiating mechanism in migraine.

Partial Text

Migraine usurps the trigeminovascular pathway (meninges, trigeminal ganglion, trigeminocervical complex, thalamus, and somatosensory cortex) to cause severe headache, with widespread dysfunction extending to additional locations due to connections with the limbic system (hypothalamus, amygdala, and hippocampus) evidenced through human [1–5] and animal studies [6]. Migraine symptoms arise from altered neuronal excitability in these pathways, but the causative mechanism that triggers abnormal excitability and symptoms remains elusive [7–9]. Cortical spreading depression (CSD) [10] is strongly supported as the basis for aura in migraine [11, 12], and experimentally-triggered CSD may produce a migraine analogue [13]. The two most frequent forms of migraine are migraine with or migraine without aura. Aura may precede migraine, yet migraine-without-aura is more common [14]; twin and genetic studies suggest that migraine with aura is different from those without aura [15, 16]. Currently, CSD remains the best candidate to initiate migraine; however, what initiates CSD or other cortical triggers [17] in migraine is not understood.

Our study design involves both human and rodent experiments. Initial measures in human migraineurs involved testing whether endogenous Na+, K+-ATPase inhibitors are detectable in CSF, whether they change in the ictal compared to interictal states, and whether they differ from levels in CSF from controls. The animal model experiments enabled more invasive testing of CSF [Na+] regulation that is not feasible in humans, using nitroglycerin that can also trigger migraine in humans.

We demonstrate, for the first time, that EOLC is protective against migraine, as evidenced by increased CSF EOLC levels during the interictal state, and decreased levels during the ictal state. This change in EOLC levels between the ictal and interictal states is independent of anti-migraine medication since their prescription usage did not change between the two sampling occasions, and they had not taken “rescue” medication before sampling. In addition, our rodent data supports cerebroventricular EOLC as a major regulator of this Na+, K+-ATPase. We also found that increasing cerebroventricular [Na+] sensitizes the preclinical rodent model, either by NTG injection or by directly infusing higher CSF [Na+]. Preventing NTG-triggered sensitization by specific inhibition of the Na+, K+-ATPase from the cerebroventricular or vascular delivery route, suggests that the choroid plexus Na+, K+-ATPase, known to be the principal regulator of CSF [Na+], is the most likely locus of the CSF [Na+] change. We report higher levels of EOLC in plasma in migraineurs compared to controls, which further support a role for altered Na+, K+-ATPase inhibitors in migraine. Plasma EOLC levels, however, do not differ between ictal and interictal states, suggesting their role reflects overall migraine biochemistry, but plasma EOLC do not protect from migraine as directly as do their CSF levels.

 

Source:

http://doi.org/10.1371/journal.pone.0218041

 

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