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: 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
• 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

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 尽管新疗法最近进步，但大部分偏头痛患者仍无法使用 已建立的治疗。对于许多患者，治疗无效，甚至是新批准的CGRP mAB 响应率仅约50％。对于其他人来说，由于禁忌症（triptans）或像阿片类药物一样，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头痛。这个插图仍然有 我们对偏头痛机制的理解的主要差距。因此，我们必须调查 涉及的潜在分子机制，旨在识别具有潜在潜力的新型治疗靶标 快速翻译到诊所。最近的数据已将腺苷A3受体（A3AR）确定为新的靶标 疼痛。我们最近的工作还确定，产生高度有害的反应性硝化物种，即 过氧亚硝酸盐（PN）导致下游修饰谷氨酸能信号和NLRP3/IL-1β驱动 神经炎症，以介导伤害性脊柱灵敏度。我们表明A3AR激动剂减弱了这些 神经性疼痛的潜水啮齿动物模型中的伤害性机制，可缓解持续的疼痛。尽管 对于三角血管偏头痛模型中的A3AR-PN机制知之甚少。但是，我们的初步 数据表明，A3AR在偏头痛疼痛的重要外围和中央区域表达 途径和A3AR激动剂抑制了几种偏头痛模型中的偏头痛反应 预测治疗效率。其他数据还暗示了PN和NLRP3的产生 偏头痛的伤害感反应。这是令人兴奋的，因为A3AR激动剂已经在非疼痛的临床试验中 疾病，具有良好的安全性，并且看起来非常适合慢性疼痛管理。基于这些 观察结果我们假设PN的产生和其下游伤害性信号传导级联 在类似偏头痛的标题和A3AR的临床前模型中参与了神经元和行为结果 激动剂通过调节该PN信号级联反应抑制这些结果。我们的目标1将是验证 A3AR是使用经过验证的急性临床前模型和急性和 慢性偏头痛的标题并确定了行为和电生理技术。我们也会 测量A3AR沿偏头痛途径的临时表达和定位。在AIM 2中，使用 药理和遗传方法，通过生化分析，我们将测试是否有益影响 通过抑制PN产生和翻译后的衰减来施加A3AR激动剂 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和 NLRP3/IL-1β驱动的神经炎症。我们的结果预计将为分子提供新颖的见解 与偏头痛中的硬脑膜 - 三角血管激活有关的神经药理学。重要的是，这些研究将 验证A3AR作为偏头痛治疗的新目标，该临床应加速“概念证明” 研究，导致新的翻译工作，以治疗偏头痛样的头痛障碍。