Peroxynitrite and Migraine

过氧亚硝酸盐和偏头痛

基本信息

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
项目类别：
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

项目摘要

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列为全球第三大流行疾病和第八大流行疾病致残（在女性中排名第四）使其成为最常见的神经系统疾病。主要原因之一偏头痛的致残性在于目前可用的治疗方法疗效不佳。低于50% 的患者通过曲坦类等急性药物获得完全缓解，只有一半的患者达到 50% 使用预防剂缓解。由于缺乏治疗手段，新疗法的开发进展缓慢了解偏头痛的潜在病理生理学。我们的长期目标是寻找新的这种常见且使人衰弱的疾病的治疗目标。偏头痛最常见的诱因之一是给予一氧化氮 (NO) 供体。大约 75% 的人类偏头痛患者会在给予 NO 供体后 6 小时内发作。 NO 供体引发偏头痛的机制尚不清楚。该提案的目的是测试 NO 与超氧化物、过氧亚硝酸盐 (PN) 的反应产物是否会导致偏头痛病理生理学。过去十年的研究表明，PN 是一种重要的激活剂/敏化剂。神经病理性疼痛、炎症性疼痛和癌症疼痛的临床前疼痛模型中的感觉神经元及其药物消除 PN 已在临床前疼痛模型中显示出功效。然而，没有研究检验过尽管观察到 PN 引发的唯一疼痛状态是否会导致偏头痛给予 PN 产生的刺激会导致偏头痛（NO 供体不会直接引起其他类型的疼痛）。因此，我们建议检验 NO 对偏头痛的影响是由于 PN 形成所致的假设。拟议研究的基本原理是：1）极大地扩展了我们对潜在机制的了解最常见的偏头痛诱因之一； 2）通过提供新的内容来提供转化潜力偏头痛的治疗目标。我们将使用临床前啮齿动物模型通过 2 个目标来检验这一假设：目标 1 将测试 PN 清除剂和分解催化剂对 NO 供体诱导的功效偏头痛行为和三叉神经（硬脑膜）神经元中 NO 供体诱导的活动。目标2将测试功效 PN清除剂和分解催化剂对抗NO供体诱导的肥大细胞脱颗粒，CGRP 释放和硬脑膜中蛋白质酪氨酸硝化。这项创新研究将首次调查 PN 在偏头痛中的作用，并将使用模仿偏头痛相关条件的新颖行为模型。这该提案的意义在于它增进了我们对偏头痛机制的理解，并具有带来更好的治疗方法的潜力。