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: 8722046
• 负责人: Michael Gordon Harrington
• 金额: $ 33.52万
• 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/8722046
• 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）：偏头痛是一种严重致残的头痛疾病，其治疗对数百万美国人来说是无效的，因为个人没有可靠的方法来预测药物反应或副作用。这些缺陷在很大程度上源于偏头痛的根本原因尚未完全了解，尽管大量研究已经揭示了神经元、血管、遗传和环境线索。然而，众所周知，神经元兴奋性的改变是偏头痛症状所固有的，了解这种兴奋性增加背后的机制是拟议工作的重点。我们的初步数据显示，人类偏头痛期间脑脊液 (CSF) 钠浓度 ([Na+]) 升高，我们发现在大鼠偏头痛模型中，大脑、CSF 和眼睛中的 [Na+] 也增加。此外，我们发现该模型中的老鼠对触摸和光的敏感性增加，这与偏头痛症状相似。根据这些结果和当前发表的生理学，我们提出了一种机制来解释偏头痛时大脑 [Na+] 如何因脑毛细血管内皮细胞 (BCEC) 中过度活跃的 Na+、K+ -ATP 酶转运蛋白 (NKAT) 过度升高。我们的理论预测，BCEC NKAT 活性高于上限会升高 [Na+]，从而增加神经元兴奋性，从而导致头痛以及对光、声音、气味和运动极度敏感。我们将通过回答三个互补的问题在大鼠偏头痛模型中测试这一理论。 1. 在行为效应开始时，大脑、脑脊液和眼睛中的 [Na+] 是否会升高，偏头痛药物是否会逆转这种变化？我们将使用国家高磁场实验室（佛罗里达州塔拉哈西）独特的 21 特斯拉 MRI 测量大脑和脑脊液 [Na+] 以及体内谷氨酸。 2. 灌注正常大脑、脑内膜和视网膜的 [Na+] 升高是否会增加神经元兴奋性？我们将利用电生理学研究大鼠大脑和眼睛中神经元的放电如何响应 [Na+] 的变化。这应该让我们知道哪些区域的神经对 [Na+] 更敏感，以及最敏感的位置是否与 MRI 研究中发现变化的区域相同。 3. BCEC NKAT 活性是否会导致大脑、颅内 CSF 和眼睛中 [Na+] 的升高？我们将在大鼠模型中比较 BCEC NKAT 的行为影响的时间和位置。我们将确定已知与偏头痛有关的区域中 BCEC NKAT 表达/活性是否发生变化，如果是，它是否会先于其他已知的偏头痛标记物（包括谷氨酸）发生变化。我们将测试抗偏头痛药物舒马曲坦和替卡格泮是否可以逆转 [Na+] 的变化，以及这是否与 BCEC NKAT 表达/活性降低相关。由于 NKAT 有许多调节因子，BCEC NKAT 过度活性会升高 [Na+]、增加神经元兴奋性并对当前偏头痛疗法做出反应，这一理论的验证将为评估和开发新疗法提供一种机制。钠和谷氨酸的客观体内生物标志物将指导动物偏头痛模型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的合理性。