CGRP's effect on hearing and balance in a mouse model of migraine

CGRP 对偏头痛小鼠模型听力和平衡的影响

• 批准号: 10174909
• 负责人: ANNE E LUEBKE
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174909
• 关键词: Affect; Agonist; Auditory system; Blocking Antibodies; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cannulas; Cerebrospinal Fluid; Chronic; Clinic; Clinical; Clinical Trials; Cochlear Nerve; Control Groups; Development; Dizziness; Equilibrium; Exhibits; Female; Fiber; Future; Goals; Headache; Hearing; Homologous Gene; Hypersensitivity; Impairment; Implant; Infusion procedures; Injections; Intraperitoneal Injections; Labyrinth; Light; Measures; Migraine; Motion Sickness; Mus; Nausea; Neurons; Neuropeptides; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phonophobias; Photophobia; Photosensitivity; Population; Posture; Pre-Clinical Model; Predisposition; RAMP1; Recovery; Recurrence; Route; Saline; Sensory; Serotonin; Signal Transduction; Symptoms; Testing; Therapeutic; Transgenic Mice; Ventricular; Vertigo; Wild Type Mouse; base; effective therapy; experience; intraperitoneal; mouse model; nervous system disorder; nestin protein; novel therapeutics; otoconia; peptide I; receptor; response; sound; translational study; triptans; vestibulo-ocular reflex

Migraine is a severe and chronic neurological disorder that affects ~18% of people worldwide, majority female (3:1). Migraine is characterized by recurrent attacks of debilitating headaches and nausea, with heightened sensory sensitivities, such as light (photophobia) and sound (phonophobia). Recently it has become recognized that ~42% of migraine patients also suffer from balance problems and dizziness, termed vestibular migraine (VM). VM is a major cause of vertigo in dizziness clinics, and is estimated to affect 1% of the overall population. Clinically, triptans (serotonin 5-HT 1B/1D receptor agonists) can reduce photophobia and headaches in migraine, but often do not relieve other VM symptoms. Thus, there is an urgent need for validated preclinical models for VM. The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a key player in migraine based on the efficacy of CGRP blockers in clinical trials against headache, and injection of CGRP triggers migraine. We have developed CGRP-sensitized transgenic mouse models for migraine that have heightened responses to light (photophobia) when CGRP is delivered either centrally or systemically. We have shown that CGRP blockers can block CGRP-induced photosensitivity in these mice, yet CGRP blockers delivered systemically cannot effectively penetrate the CNS, and these blockers are not effective against centrally-induced photophobia, suggesting that photosensitivity in migraine involves both systemic and central components. CGRP is also widely distributed throughout the vestibular CNS, and CGRP-containing efferent fibers project to all inner ear endorgans. CGRP is also signaling in the vestibular and auditory systems, as we discovered in a different mouse model, that the loss of CGRP reduces the vestibulo-ocular reflex (VOR) gain, reduces otolith- evoked dynamics reduces, reduces sound-evoked activity in the cochlear nerve, and impairs rotarod (balance) performance. Yet, it is not yet known if CGRP is acting centrally or peripherally in VM; which would influence treatment routes and efficacy. We propose to measure mouse homologues of clinical VM symptoms namely; phonophobia, imbalance, nausea, and motion-sickness susceptibility; and will investigate these measures in three mouse lines: i) wildtype (WT) littermate controls and CGRP-sensitized mouse models with ii) neuronally- sensitized CGRP receptors (nestinRAMP1) or iii) globally-sensitized CGRP receptors (global RAMP1). Our hypothesis is that elevated CGRP-sensitivity will contribute to increased sensitivities found in VM; and that these VM symptoms will be ameliorated by CGRP blockers. Information gained from these studies will provide a direct assessment of whether CGRP-sensitized mouse models that have been shown to mirror the photophobia of migraine, can also mirror deficits observed in VM. Such a preclinical model of VM could be used for future translational studies to develop and test new therapeutics. !

偏头痛是一种严重的慢性神经系统疾病，全世界约有18%的人受到影响，其中大多数人 女性(3：1)。偏头痛的特点是反复发作衰弱的头痛和恶心， 感官敏感度提高，如光(畏光)和声音(恐音)。最近，它已经 人们认识到，大约42%的偏头痛患者也有平衡问题和头晕，称为 前庭偏头痛(VM)。VM是头晕诊所中导致眩晕的主要原因，估计影响1%的 总人口。临床上，雷公藤甲素(5-HT1B/1D受体激动剂)可以减少畏光 偏头痛和头痛，但通常不能缓解其他VM症状。因此，迫切需要 已验证的VM临床前模型。 神经肽降钙素基因相关肽(CGRP)被认为在偏头痛中起关键作用 关于降钙素基因相关肽阻滞剂治疗头痛的临床试验，以及注射降钙素基因相关肽引发偏头痛。 我们已经开发出CGRP致敏的偏头痛转基因小鼠模型，该模型具有高反应性 当CGRP以中央或系统方式递送时，会导致光(恐光症)。我们已经证明了CGRP 在这些小鼠中，阻滞剂可以阻断CGRP诱导的光敏反应，但CGRP阻滞剂是全身注射的 不能有效地穿透中枢神经系统，这些阻滞剂对中枢诱导的 光恐惧症，表明偏头痛的光敏性涉及全身和中枢两个组成部分。 降钙素基因相关肽也广泛分布于前庭中枢神经系统，含降钙素基因相关肽的传出纤维投射到 所有内耳内脏。降钙素基因相关肽也在前庭和听觉系统中发出信号，正如我们在 不同的小鼠模型，CGRP的丢失降低了前庭-眼反射(VOR)的增益，减少了耳石- 诱发动力学减少，减少了耳蜗神经中的声音诱发活动，并损害了旋转臂(平衡)。 性能。然而，目前尚不清楚CGRP在VM中是中枢还是外周作用；这将影响 治疗路线和疗效。我们建议测量临床VM症状的小鼠同源物，即； 恐音症、失衡、恶心和晕动病易感性；并将在 三个小鼠品系：i)野生型(WT)仔鼠对照和CGRP致敏小鼠模型 敏化的CGRP受体(NestinRAMP1)或III)全局敏化的CGRP受体(GLOBAL RAMP1)。我们的 假设降钙素基因相关肽敏感性升高将有助于VM的敏感性增加；以及 这些VM症状将通过CGRP阻滞剂得到改善。 从这些研究中获得的信息将直接评估CGRP致敏的小鼠 已被证明可以反映偏头痛恐光症状的模型，也可以反映在VM中观察到的缺陷。 这种VM的临床前模型可以用于未来的翻译研究，以开发和测试新的 治疗学。好了！