Dysfunction of sodium homeostasis in a rat migraine model

大鼠偏头痛模型中钠稳态功能障碍

• 批准号: 8516124
• 负责人: Michael Gordon Harrington
• 金额: $ 32.68万
• 依托单位: HUNTINGTON MEDICAL RESEARCH INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516124
• 关键词: ATP phosphohydrolase; Action Potentials; Adverse effects; American; Animals; Area; Behavioral; Biochemical; Biological Assay; Biological Markers; Blood; Blood Vessels; Blood capillaries; Brain; Capillary Endothelial Cell; Cell Culture Techniques; Cerebrospinal Fluid; Ciliary Body; Data; Disease; Dura Mater; Electron Microscopy; Electrophysiology (science); Eye; Functional disorder; Genetic; Glutamates; Handedness; Headache; Headache Disorders; Homeostasis; Human; Immunohistochemistry; Individual; K ATPase; Knowledge; Laboratories; Lead; Light; Location; Magnetic Resonance Imaging; Measures; Migraine; Modeling; Motion; Na(+)-K(+)-Exchanging ATPase; Nerve; Neurons; Neurotransmitters; Nitroglycerin; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Photophobia; Physiology; Plant Roots; Potassium; Publishing; Rattus; Reporting; Research; Retina; Role; Rosa; Serotonin; Serotonin Agonists; Site; Smell Perception; Sodium; Sodium Glutamate; Somatosensory Cortex; Staging; Structure of choroid plexus; Structure of trigeminal ganglion; Sumatriptan; Symptoms; Testing; Thalamic structure; Time; Touch sensation; Trigeminal Nuclei; Variant; Vitreous humor; Work; allodynia; base; central sensitization; improved; in vivo; light microscopy; magnetic field; midbrain central gray substance; neuronal excitability; response; simulation; sound; stem; theories

DESCRIPTION (provided by applicant): Migraine is a severely disabling headache disorder for which treatment is ineffective for millions of Americans, because individuals have no reliable way to predict drug responses or side effects. These shortcomings stem in large part because the root cause of migraine is not fully understood, even though a substantial body of research has revealed neuronal, vascular, genetic, and environmental clues. It is well established, however, that altered neuronal excitability is inherent to migraine symptoms, and understanding the mechanism behind this increased excitation is the focus of the proposed work. Our preliminary data show a rise in cerebrospinal fluid (CSF) sodium concentration ([Na+]) during migraine in humans and we found that the [Na+] also increased in the brain, CSF, and eyes in a rat migraine model. Moreover, we found rats in this model have increased sensitivity to touch and light that are similar to migraine symptoms. From these results and current published physiology, we propose a mechanism to explain how brain [Na+] rises excessively in migraine from overactive Na+, K+ -ATPase transporters (NKATs) in brain capillary endothelial cells (BCECs). Our theory predicts that BCEC NKAT activity above an upper limit elevates [Na+], increasing neuronal excitability that causes the headache and extreme sensitivity to light, sound, smells, and motion. We will test this theory in the rat migraine model by answering three complementary questions. 1. Does [Na+] rise in brain, CSF, and eyes at the beginning of the behavioral effects, and does migraine medication reverse the changes? We will measure brain and CSF [Na+] and glutamate in vivo using the unique 21 Tesla MRI at the National High Magnetic Field Laboratory (Tallahassee, FL). 2. Does rising [Na+] that perfuses the normal brain, brain lining, and retina increase neuronal excitability? We will study how the firing of neurons in the rat brain and eyes responds to changes in [Na+] using electrophysiology. This should let us know in what regions nerves are more sensitive to [Na+] and whether the locations that are most sensitive are the same as those areas found to change in the MRI studies. 3. Does BCEC NKAT activity lead to the rise of [Na+] in the brain, intracranial CSF, and eyes? We will compare the timing and locations of the behavioral effects with BCEC NKATs in the rat model. We will determine if BCEC NKAT expression/activity changes in regions known to be involved in migraine and, if so, does it change before other known markers of migraine, including glutamate. We will test if the anti-migraine medications sumatriptan and telcagepant reverse the [Na+] changes, and if this correlates with decreased BCEC NKAT expression/activity. Verification of our theory that BCEC NKAT overactivity elevates [Na+], increases neuronal excitability, and responds to current migraine therapies will provide a mechanism to evaluate and develop new treatments, since NKATs have many regulators. Objective in vivo biomarkers of sodium and glutamate will guide further research of pathophysiology in the animal migraine model, and will justify efforts to apply this to humans.

描述（由申请人提供）：偏头痛是一种严重残疾的头痛障碍，对于数百万美国人而言，治疗无效，因为个人没有可靠的方法来预测药物反应或副作用。这些缺点在很大程度上是因为偏头痛的根本原因尚未完全理解，尽管大量研究表明神经元，血管，遗传和环境线索。然而，良好的神经元兴奋性是偏头痛症状所固有的，理解这种增加的兴奋背后的机制是拟议工作的重点。我们的初步数据表明，人类偏头痛期间脑脊液（CSF）钠浓度（[Na+]）的增加，我们发现在大鼠偏头痛模型中，[Na+]在大脑，CSF和眼睛中也增加了[Na+]。此外，我们发现该模型中的大鼠对触摸和光的敏感性增加了与偏头痛症状相似的敏感性。从这些结果和当前已发表的生理学中，我们提出了一种机制，可以解释脑部在偏头痛中如何从过度活跃的Na+，K+-ATPase Transporters（NKAT）中过度上升，脑毛细管内皮细胞（BCEC）。我们的理论预测，BCEC NKAT活性高于上限，可以提高[Na+]，从而增加了神经元兴奋性，从而引起对光，声音，气味和运动的头痛和极端敏感性。我们将通过回答三个互补问题来测试大鼠偏头痛模型中的理论。 1。在行为效应开始时[NA+]在大脑，CSF和眼睛的上升吗？偏头痛药物是否会逆转变化？我们将使用在国家高磁场实验室（佛罗里达州塔拉哈西）的独特21 Tesla MRI测量体内大脑和CSF [Na+]和谷氨酸。 2。灌注正常大脑，脑内衬和视网膜的升高[Na+]会增加神经元兴奋性吗？我们将研究大鼠脑和眼睛中神经元的发射如何使用电生理学对[Na+]的变化做出反应。这应该让我们知道哪些区域神经对[Na+]更敏感，以及最敏感的位置是否与在MRI研究中发现的那些区域相同。 3。BCEC NKAT活性是否导致脑内CSF和眼睛中[Na+]的兴起？我们将将行为效应的时间和位置与大鼠模型中的BCEC NKAT进行比较。我们将确定已知与偏头痛有关的区域的BCEC NKAT表达/活性变化，如果是的，则它是否在包括谷氨酸在内的其他已知偏头痛标记之前发生了变化。我们将测试抗毛因药物sumatriptan和telcagepant是否会逆转[Na+]的变化，并且这是否与BCEC NKAT表达/活性降低相关。验证我们的理论是，BCEC NKAT过度活动会提高[NA+]，提高神经元兴奋性并对当前的偏头痛疗法做出反应，因为NKAT具有许多调节剂，因此可以提供一种评估和开发新疗法的机制。钠和谷氨酸的体内生物标志物的客观将指导动物偏头痛模型中的病理生理学的进一步研究，并将证明将其应用于人类的努力是合理的。