Molecular basis for adenosine A3 receptor agonists in the treatment of migraine

腺苷A3受体激动剂治疗偏头痛的分子基础

基本信息

批准号：
10363152
负责人：
Simon Akerman
金额：
$ 49.89万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363152
关键词：
Acute Address Adenosine A3 Receptor Adult Affect Agonist Analgesic Overuse Headaches Attenuated Behavioral Biochemical Biochemical Pathway Blood Platelets Cephalic Chronic Clinic Clinical Research Clinical Trials Cutaneous Data Development Dose Electrophysiology (science)Family Female Glutamates Goals Headache Headache Disorders Hypersensitivity Inflammation Inflammatory Interleukin-1 Interleukin-1 beta Investigation Knockout Mice Link Measures Mediating Medical Migraine Modeling Modification Molecular Molecular Target Monoclonal Antibodies Neurons Neuropharmacology Nociception Opioid Outcome Pain Pathway interactions Patients Peripheral Peroxonitrite Persistent pain Pharmacology Pilot Projects Population Post-Translational Protein Processing Pre-Clinical Model Preventive Process Production Proteins Public Health Publishing Receptor Activation Reporting Rodent Rodent Model Role Safety Serum Signal Transduction Specificity Spinal Structure of trigeminal ganglion Techniques Testing Therapeutic Therapeutic Intervention Time Translations Treatment Efficacy Trigeminal Nuclei Trigeminal System Work antagonist attenuation base behavioral outcome chronic pain management clinical translation cytokine genetic approach glutamatergic signaling insight interdisciplinary approach male marenostrin migraine treatment neuroinflammation neuronal excitability neurotransmission new therapeutic target nociceptive response non-opioid analgesic novel novel therapeutic intervention novel therapeutics pain model pain relief painful neuropathy receptor response socioeconomics somatosensory triptans

项目摘要

Project Summary/Abstract Despite recent advances with new therapies, a huge proportion of migraine patients are still unable to use established therapeutics. For many patients, treatments are not effective, even newly approved CGRP mAbs have response rates of only ~50%. For others they are unsafe due to contraindications (triptans), or like opioids, not suited for long term use, even exacerbating existing migraine headache. This illustrates that there are still major gaps in our understanding of migraine mechanisms. It is therefore imperative that we investigate the underlying molecular mechanisms involved, geared towards identifying novel therapeutic targets with potential for rapid translation to the clinic. Recent data have identified the adenosine A3 receptor (A3AR) as a novel target for pain. Our recent work has also established that production of the highly noxious reactive nitroxidative species, peroxynitrite (PN), causes downstream modifications to glutamatergic signaling and NLRP3/IL-1β-driven neuroinflammation, to mediate nociceptive spinal sensitization. We show that A3AR agonists attenuate these nociceptive mechanisms in diverse rodent models of neuropathic pain, providing persistent pain relief. Despite this, little is known about A3AR-PN mechanisms in trigeminovascular migraine models. However, our preliminary data demonstrate that A3AR are expressed in important peripheral and central regions along the migraine pain pathway, and A3AR agonists inhibit migraine-like responses in several rodent models of migraine that are highly predictive of therapeutic efficacy. Additional data also implicate both PN and NLRP3 production in mediating migraine-like nociceptive responses. This is exciting as A3AR agonists are already in clinical trials in non-pain disorders, have a good safety profile, and appear well suited for chronic pain management. Based on these observations we hypothesize that PN production and activation of its downstream nociceptive signaling cascade is involved in neuronal and behavioral outcomes in preclinical models of migraine-like headache, and A3AR agonists inhibit these outcomes, via modulation of this PN signaling cascade. Our goal in Aim 1 will be to validate A3AR as a novel therapeutic target for migraine-like headache using validated preclinical models of acute and chronic migraine-like headache and established behavioral and electrophysiological techniques. We will also measure the temporal expression and localization of A3AR along the migraine pain pathway. In Aim 2, using pharmacological and genetic approaches, with biochemical analyses, we will test whether the beneficial effects of A3AR agonists are exerted through inhibition of PN production, and attenuation of post-translational modifications to neuronal and glial proteins involved in nociceptive glutamatergic neurotransmission and NLRP3/IL-1β-driven neuroinflammation. Our results are anticipated to provide novel insights into the molecular neuropharmacology related to dural-trigeminovascular activation in migraine. Importantly, these studies will validate A3AR as a novel target for migraine treatment, which should accelerate ‘proof-of-concept’ clinical studies, leading to a new translational effort in the treatment of migraine-like headache disorders.

项目概要/摘要尽管新疗法最近取得了进展，但很大一部分偏头痛患者仍然无法使用对于许多患者来说，即使是新批准的 CGRP 单克隆抗体，治疗也无效。对于其他人来说，由于禁忌症（曲坦类药物）或阿片类药物，它们是不安全的。不适合长期使用，甚至会加剧现有的偏头痛。我们对偏头痛机制的理解存在重大差距，因此我们有必要对其进行调查。涉及的潜在分子机制，旨在识别具有潜在潜力的新治疗靶点最近的数据已确定腺苷 A3 受体 (A3AR) 为新靶点。我们最近的工作还确定了剧毒活性硝基氧化物质的产生，过氧亚硝酸盐 (PN)，导致谷氨酸信号传导和 NLRP3/IL-1β 驱动的下游修饰神经炎症，介导伤害性脊髓敏化我们发现 A3AR 激动剂可以减弱这些症状。不同啮齿动物神经性疼痛模型中的伤害感受机制，提供持续的疼痛缓解。然而，我们对三叉血管性偏头痛模型中 A3AR-PN 的机制知之甚少。数据表明 A3AR 在偏头痛沿的重要外周和中心区域表达途径，A3AR 激动剂可抑制多种偏头痛啮齿动物模型中的偏头痛样反应，这些反应高度额外的数据还表明 PN 和 NLRP3 的产生均具有调节作用。偏头痛样伤害性反应令人兴奋，因为 A3AR 激动剂已经在非疼痛方面进行临床试验。疾病，具有良好的安全性，并且基于这些似乎非常适合慢性疼痛管理。我们观察到 PN 的产生及其下游伤害性信号级联的激活参与偏头痛样头痛和 A3AR 临床前模型的神经元和行为结果激动剂通过调节 PN 信号级联抑制这些结果，我们的目标 1 是验证。 A3AR 作为偏头痛样头痛的新型治疗靶点，使用经过验证的急性和慢性临床前模型我们还将研究慢性偏头痛样头痛以及已建立的行为和电生理技术。使用目标 2 测量 A3AR 沿偏头痛通路的时间表达和定位。药理学和遗传学方法，通过生化分析，我们将测试是否有有益效果 A3AR 激动剂的作用是通过抑制 PN 产生和减弱翻译后对参与伤害性谷氨酸能神经传递的神经元和神经胶质蛋白的修饰 NLRP3/IL-1β 驱动的神经炎症有望为分子机制提供新的见解。重要的是，这些研究将与偏头痛的硬脑膜三叉神经血管激活相关。验证 A3AR 作为偏头痛治疗的新靶点，这将加速“概念验证”临床研究，导致了治疗偏头痛样头痛疾病的新转化努力。