Peroxynitrite and Migraine

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最常见疾病 致残(在女性中排名第四)使其成为最常见的神经疾病。其中一个主要原因是 由于偏头痛的致残性，目前可用的治疗方法疗效不佳。低于50% 的患者用雷公藤甲素等急性剂完全缓解，只有一半的患者达到50% 使用预防性药物缓解症状。由于缺乏药物，新疗法的发展一直很缓慢。 了解偏头痛的潜在病理生理学。我们的长期目标是发现新的 治疗这种常见和令人衰弱的疾病的靶点。 偏头痛最稳定的诱因之一是服用一氧化氮(NO)供体。大致 75%的人类偏头痛患者会在没有供体治疗的6小时内发作。 没有捐赠者引发偏头痛的机制尚不清楚。这项提议的目标是测试 一氧化氮和超氧化物的反应产物过氧亚硝酸盐(PN)是否与偏头痛有关 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、炎症性和癌性疼痛的临床前疼痛模型中的感觉神经元以及 消除PN已在临床前疼痛模型中显示出有效性。然而，还没有研究检查过 PN是否有助于偏头痛，尽管观察到唯一由 给予PN产生的刺激是偏头痛(没有捐赠者不会直接引起其他类型的疼痛)。 因此，我们建议检验这一假设，即NO对偏头痛的影响是由于PN的形成。 这项拟议研究的基本原理是：1)它极大地扩展了我们对潜在机制的认识 最常见的偏头痛诱因之一；和2)通过提供新的 偏头痛的治疗靶点。我们将使用临床前啮齿动物模型来验证这一假设，目的有两个： 目标1将测试净光合酶清除剂和分解催化剂对NO供体诱导的效果 偏头痛行为和NO供体诱导的三叉神经(硬脑膜)神经元活动。目标2将测试疗效 PN清除剂和分解催化剂对NO供体诱导的肥大细胞脱颗粒的影响 硬脑膜中的蛋白质酪氨酸硝化。这项创新的研究将首次调查 PN在偏头痛中的作用，并将使用新的行为模型来模拟与偏头痛相关的条件。这个 这项建议的意义在于，它促进了我们对偏头痛机制的理解，并具有 有可能带来更好的治疗方法。

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.