Dysfunction of Sodium Homeostasis in Migraine

从1990年到2016年，偏头痛位居前五位的原因是“多年来生活在残疾”。即使是好的 诊断和治疗(Triptans、Gepants、Ditans和Glurant)，许多人仍然残疾。盛行的 三叉神经血管理论指出了神经元和血管成分的组合，但 偏头痛为什么以及何时开始的基本机制仍不清楚。我们的大前提是 引发偏头痛的各种诱因，或抑制偏头痛的药物，通过共同的途径发挥作用；发现 这一机制将提供一种更有凝聚力的治疗偏头痛的策略，这是对经验证据的补充 接近。我们提出了一种改变脑脊液钠离子浓度的共同途径。 在我们最近的RO1NS072497项目中：“偏头痛大鼠模型的钠稳态功能障碍。”在这 硝酸甘油(NTG)触发的模型，我们证明[Na+]主要在脑室脑脊液中增加，使用 23Na核磁共振。在人类中，我们发现偏头痛期间脑脊液[Na+]较高，这已在一项研究中得到证实 最近报道的对偏头痛的独立研究，也使用了23Na磁共振成像。探索……之间的关系 偏头痛的[Na+]升高和超敏反应，我们证明高细胞外[Na+]升高 在模拟、神经细胞和活体中的神经元兴奋性；这种影响可以通过以下方式来模拟 直接增加脑室内[Na+]；抑制Na，K-ATPase可阻止NTG效应 定位于脉络丛(CP)上皮。这些结果表明，伤害性感受来自神经元。 沿脑室和硬膜下脑脊液途径暴露于较高的细胞外[Na+]。我们的中央 假设偏头痛的触发因素改变了CP的Na，K-ATPase活性和脑脊液[Na+]稳态， 这会改变神经元的兴奋性并引发偏头痛。我们的假设预测，大多数 成功的治疗将纠正改变的Na，K-ATPase稳态。我们将验证并 检测大鼠NTG模型(AIM 1a)脑脊液中CP-Na，K-ATPase活性及[Na+]的变化 CP如何改变(目标1b)，以及脑脊液和脑组织[Na+]如何变化(目标1c和d)。我们会 测量脑组织的代谢和三叉神经血管变化(目标1e)，并检查这些变化如何 这些特征与脑脊液[Na+]和CP Na，K-ATPase活性有关。Aim 2将测试典型的偏头痛药物 (舒马曲坦和telcagant)拯救NTG触发的伤害性感受。这些研究有可能 支持低剂量和安全剂量的地高辛的再利用(目前用于心脏病学的剂量的1/100)以抑制 降低脑脊液Na，K-ATPase活性，防止脑脊液[Na+]升高。这些实验将证明未来的努力是正确的 优化新的调节剂，以调节CP Na，K-ATPase和CSF[Na+]生物标志物。潜在的 通过调整CP和CSF改善脑内稳态[Na+]生物标志物可能延伸至其他波动的生物标志物 失调，如偏头痛合并疼痛和情绪状况。

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.