Alternative signaling pathways to CGRP in the generation of migraine attacks

偏头痛发作中 CGRP 的替代信号通路

• 批准号: 511904807
• 负责人: Dr. Bianca Raffaelli
• 金额: --
• 依托单位: Klinik für Neurologie mit Experimenteller Neurologie (CCM)
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/511904807?language=en
• 关键词: Alternative; signaling; pathways; CGRP; generation

Migraine is a frequent and debilitating neurological disease with a complex pathophysiology. The neuropeptide calcitonin gene-related peptide (CGRP) plays a crucial role in the generation of migraine attacks. During a migraine attack, CGRP is released from trigeminal afferents and triggers an inflammatory response. In recent years, monoclonal antibodies against the CGRP signaling pathway have proven effective in migraine prevention. However, not all patients respond to CGRP-targeted treatment. Approximately 20% of patients treated with CGRP(-receptor) antibodies show no change in their migraine frequency and even good responders still report frequent migraine attacks. Migraine provocation studies have shown that only two-thirds of patients develop a migraine attack after intravenous administration of CGRP. This suggests that other molecular signaling pathways besides CGRP are involved in the development of migraine attacks. A current pathophysiological model proposes the opening of adenosine triphosphate-sensitive potassium (KATP) channels as the final step in the intracellular signaling cascade of migraine. Indeed, the KATP channel opener levcromakalim triggered migraine attacks in all examined patients. Various inflammatory neuropeptides can lead to the opening of KATP channels by binding to G-protein-coupled receptors. These include, besides CGRP, pituitary adenylate cyclase-activating polypeptide (PACAP-38) and other members of the calcitonin family such as adrenomedullin and amylin.The aim of this project is to investigate these other nociceptive signaling pathways in the development of migraine attacks. To prevent the activation of the CGRP pathway, the CGRP receptor will be blocked by the monoclonal antibody erenumab. The project consists of two subprojects. The first subproject is a placebo-controlled provocation study with levcromakalim in patients receiving erenumab therapy. According to the presented pathophysiogical model, migraine attacks triggered by levcromakalim should bypass a blockade of the CGRP receptor. The activation of KATP channels by other neuropeptides could explain why patients still develop frequent migraine attacks under erenumab treatment. The second subproject investigates changes in PACAP-38, adrenomedullin and amylin concentrations under erenumab therapy. The blockade of the CGRP receptor could lead to compensatory upregulation of these nociceptive signaling pathways. On the other hand, if these pathways are truly independent, no relevant changes are expected. The investigation of alternative inflammatory signaling pathways is crucial to explain the interindividual differences in the therapeutic response to CGRP-targeted therapies. Dissecting these molecular mechanisms will help identify new therapeutic approaches for the preventive treatment of migraine.

偏头痛是一种常见的神经系统疾病，具有复杂的病理生理机制。神经肽降钙素基因相关肽（CGRP）在偏头痛发作的产生中起着至关重要的作用。在偏头痛发作期间，CGRP从三叉神经传入神经释放并引发炎症反应。近年来，针对CGRP信号通路的单克隆抗体已被证明在偏头痛预防中有效。然而，并非所有患者都对CGRP靶向治疗有反应。大约20%的CGRP（受体）抗体治疗的患者显示他们的偏头痛频率没有变化，甚至良好的反应者仍然报告频繁的偏头痛发作。偏头痛激发研究表明，只有三分之二的患者在静脉注射CGRP后发生偏头痛发作。这表明除了CGRP之外的其他分子信号传导途径参与了偏头痛发作的发展。目前的病理生理学模型提出，三磷酸腺苷敏感性钾（KATP）通道的开放是偏头痛细胞内信号级联的最后一步。事实上，KATP通道开放剂levcromakalim在所有接受检查的患者中都引发了偏头痛发作。各种炎症性神经肽可通过与G蛋白偶联受体结合导致KATP通道开放。这些包括，除了CGRP，垂体腺苷酸环化酶激活多肽（PACAP-38）和降钙素家族的其他成员，如肾上腺髓质素和胰淀素。为了防止CGRP途径的激活，CGRP受体将被单克隆抗体erenumab阻断。该项目包括两个分项目。第一个子项目是在接受erenumab治疗的患者中进行的左克罗卡林安慰剂对照激发研究。根据所提出的病理生理模型，由左克罗卡林引发的偏头痛发作应绕过CGRP受体的阻断。其他神经肽激活KATP通道可以解释为什么患者在erenumab治疗下仍然发生频繁的偏头痛发作。第二子项目研究了erenumab治疗下PACAP-38、肾上腺髓质素和胰淀素浓度的变化。CGRP受体的阻断可导致这些伤害性信号传导途径的补偿性上调。另一方面，如果这些途径是真正独立的，预计不会有相关的变化。 替代性炎症信号通路的研究对于解释CGRP靶向治疗反应的个体间差异至关重要。剖析这些分子机制将有助于确定新的治疗方法，预防性治疗偏头痛。