Peroxynitrite and Migraine

过氧亚硝酸盐和偏头痛

• 批准号: 9753377
• 负责人: GREGORY O DUSSOR
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753377
• 关键词: Acute; Address; Afferent Neurons; Arginine; Auras; Behavior; Behavioral Model; Biological Assay; Blood Platelets; Calcitonin Gene-Related Peptide; Cell Degranulation; Chronic; Common Migraine; Data; Development; Disease; Dose; Dura Mater; Face; Functional disorder; Goals; Gold; Headache; Hour; Human; Hypersensitivity; Inflammation; Interleukin-6; Knowledge; Lead; Measures; Mediating; Migraine; Modeling; Mus; Nature; Neurons; Neuropeptides; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthetase Inhibitor; Nitroglycerin; Oral; Pain; Pain-Free; Patients; Peroxonitrite; Pharmacology; Phase; Physiological; Preclinical Testing; Production; Proteins; Rattus; Reaction; Reporting; Rodent; Rodent Model; Role; Source; Stimulus; Stress; Sumatriptan; Superoxides; Symptoms; Testing; Therapeutic; Time; Trigeminal System; Tyrosine; Woman; World Health Organization; base; cancer pain; catalyst; efficacy testing; experimental study; inflammatory pain; inhibitor/antagonist; innovation; mast cell; nervous system disorder; new therapeutic target; nitration; novel; novel therapeutic intervention; novel therapeutics; omega-N-Methylarginine; pain model; painful neuropathy; pre-clinical; prevent; response; restraint stress; triptans

The World Health Organization ranks migraine as the 3rd most prevalent disease worldwide and 8th most disabling (4th most in women) making it the most common neurological disorder. One of the primary reasons for the disabling nature of migraine is the poor efficacy of currently available therapeutics. Less than 50% of patients achieve complete relief with acute agents such as triptans and only half of patients achieve 50% relief with preventative agents. Development of new therapeutics has been slow due to a lack of understanding of the underlying pathophysiology of migraine. Our long-term goal is to identify new therapeutic targets for this common and debilitating disorder. One of the most consistent triggers for migraine is administration of a nitric oxide (NO) donor. Approximately 75% of human migraine patients will develop an attack within 6 hours of NO donor administration. Mechanisms by which NO donors trigger migraine are unknown. The objective of this proposal is to test whether the reaction product of NO and superoxide, peroxynitrite (PN), contributes to migraine pathophysiology. Studies over the last decade have shown that PN is an important activator/sensitizer of sensory neurons in preclinical pain models of neuropathic, inflammatory, and cancer pain and agents that eliminate PN have demonstrated efficacy in preclinical pain models. However, no studies have examined whether PN contributes to migraine despite the observation that the only pain state triggered by administration of a PN-producing stimulus is migraine (NO donors do not directly cause other types of pain). Thus, we propose to test the hypothesis that the effects of NO on migraine are due to PN formation. The rationale for the proposed study is that it 1) greatly expands our knowledge of mechanisms underlying one of the most common migraine triggers; and 2) provides translational potential by offering new therapeutic targets for migraine. We will test this hypothesis with 2 Aims using preclinical rodent models: Aim 1 will test the efficacy of PN scavengers and decomposition catalysts against NO donor-induced migraine behavior and NO donor-induced activity in trigeminal (dural) neurons. Aim 2 will test the efficacy of PN scavengers and decomposition catalysts against NO donor-induced mast cell degranulation, CGRP release, and protein tyrosine nitration in the dura. This innovative study will for the first time investigate the role of PN in migraine and will use novel behavioral models that mimic conditions relevant to migraine. The significance of the proposal is that it advances our understanding of migraine mechanisms and has the potential to lead to better therapeutics.

世界卫生组织将偏头痛排名为全球第三种疾病，第八名 使其成为最常见的神经系统疾病（女性中最高的第四名）。主要原因之一 对于偏头痛的致残性质是当前可用的治疗剂的效力不佳。小于50％ 在急性剂（例如triptans）和只有一半的患者的患者中，有50％ 预防代理人的缓解。由于缺乏 了解偏头痛的基础病理生理学。我们的长期目标是确定新的 这种常见和使人衰弱障碍的治疗靶标。 偏头痛最一致的触发因素之一是给予一氧化氮（NO）供体。大约 75％的人类偏头痛患者将在不给予捐助者的6小时内发生攻击。 没有捐助者触发偏头痛的机制未知。该建议的目的是测试 NO和超氧化物（PN）的反应产物是否有助于偏头痛 病理生理学。过去十年的研究表明，PN是重要的激活剂/敏化器 神经性，炎症性和癌症疼痛和药物的临床前疼痛模型中的感觉神经元 消除PN在临床前疼痛模型中表现出功效。但是，没有研究 尽管观察到唯一触发的疼痛状态，但PN是否有助于偏头痛 产生PN的刺激是偏头痛（没有供体不会直接引起其他类型的疼痛）。 因此，我们建议检验以下假设：NO对偏头痛的影响是由于PN形成。 拟议的研究的理由是，它是1）大大扩展了我们对机制的知识 最常见的偏头痛触发因素之一； 2）通过提供新的方式提供翻译潜力 偏头痛的治疗靶标。我们将使用临床前啮齿动物模型通过2个目标检验这一假设： AIM 1将测试PN清除剂和分解催化剂的功效 偏头痛行为，没有供体诱导的三叉神经元的活性。 AIM 2将测试功效 pN清除剂和分解催化剂，抗捐赠者诱导的肥大细胞脱粒，CGRP 在硬脑膜中释放和蛋白酪氨酸硝化。这项创新的研究将首次研究 PN在偏头痛中的作用，并将使用与偏头痛相关的新型行为模型。这 该提案的意义是，它促进了我们对偏头痛机制的理解，并具有 潜力导致更好的治疗疗法。