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

• 批准号: 10532300
• 负责人: Simon Akerman
• 金额: $ 47.29万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/10532300
• 关键词: Acceleration; 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; Disease; Dose; Electrophysiology (science); Family; Female; Glutamates; Goals; Headache; Headache Disorders; Hypersensitivity; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Investigation; Knockout Mice; Link; Measures; Mediating; Medical; Migraine; Modeling; Modification; Molecular; Molecular Target; Monoclonal Antibodies; Neuroglia; 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; Vertebral column; Work; antagonist; attenuation; behavioral outcome; chronic pain management; clinical translation; comparison control; 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; pharmacologic; receptor; response; socioeconomics; somatosensory; triptans

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.

项目摘要/摘要 尽管最近在新疗法方面取得了进展，但仍有很大一部分偏头痛患者无法使用 成熟的治疗方法。对于许多患者来说，治疗是无效的，即使是新批准的CGRP单抗 应答率只有~50%。对于其他人来说，由于禁忌症(Triptans)或类似阿片类药物，它们是不安全的， 不适合长期使用，甚至会加重现有的偏头痛。这说明，仍有 在我们对偏头痛机制的理解上存在重大差距。因此，我们当务之急是调查 涉及的潜在分子机制，旨在发现具有潜力的新治疗靶点 以便快速转送到诊所。最近的数据表明，腺苷A3受体(A3AR)是一个新的靶点 止痛。我们最近的工作还证实，生产剧毒的反应性氮氧化物物种， 过氧亚硝酸盐(PN)引起谷氨酸能信号和NLRP3/IL-1β驱动的下游修饰 神经炎症，以介导脊髓伤害性敏感化。我们发现A3AR激动剂可以减弱这些 神经病理性疼痛的不同啮齿动物模型的伤害性机制，提供持续性疼痛缓解。尽管 这一点，关于A3AR-PN在三叉神经血管性偏头痛模型中的机制知之甚少。然而，我们的初步调查 数据表明，A3AR在偏头痛沿线的重要外周和中央区域有表达 途径和A3AR激动剂抑制几种高度偏头痛啮齿动物模型的偏头痛样反应 治疗效果的预测。更多数据也表明Pn和NLRP3产量在调节 偏头痛样伤害性反应。这是令人兴奋的，因为A3AR激动剂已经在无痛的临床试验中 具有良好的安全性，并且似乎非常适合慢性疼痛的治疗。基于这些 观察我们假设Pn的产生和下游伤害性信号的激活级联 参与了偏头痛和A3AR临床前模型的神经和行为结果 激动剂通过调节这一PN信号级联来抑制这些结果。我们在目标1中的目标是验证 A3AR作为治疗偏头痛样头痛的新靶点 慢性偏头痛和已建立的行为和电生理技术。我们还将 测定A3AR在偏头痛痛通路中的时间表达和定位。在目标2中，使用 药理学和遗传学的方法，结合生化分析，我们将测试是否有有益的效果 的A3AR激动剂是通过抑制Pn的产生和翻译后的减弱而发挥作用的 参与伤害性谷氨酸能神经传递的神经元和胶质蛋白的修饰 NLRP3/IL-1β诱导的神经炎症。我们的结果有望为我们提供对分子的新见解。 偏头痛与硬脑膜-三叉神经血管激活相关的神经药理学。重要的是，这些研究将 验证A3AR作为偏头痛治疗的新靶点，这应该会加速临床的“概念验证” 研究，导致了治疗偏头痛样头痛障碍的新的翻译努力。