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.

偏头痛是一种常见且使人衰弱的神经系统疾病，具有复杂的病理生理学。神经肽降钙素基因相关肽（CGRP）在偏头痛发作中起着至关重要的作用。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可有效预防偏头痛。然而，并非所有患者都对 CGRP 靶向治疗有反应。大约 20% 接受 CGRP（受体）抗体治疗的患者偏头痛频率没有变化，甚至反应良好的患者仍然报告偏头痛频繁发作。偏头痛激发研究表明，只有三分之二的患者在静脉注射 CGRP 后出现偏头痛发作。这表明除 CGRP 之外的其他分子信号传导途径也参与偏头痛发作的发生。目前的病理生理学模型提出，三磷酸腺苷敏感钾（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 引发了所有接受检查的患者的偏头痛发作。多种炎症神经肽可通过与 G 蛋白偶联受体结合导致 KATP 通道打开。除 CGRP 外，这些还包括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，例如肾上腺髓质素和胰淀素。该项目的目的是研究偏头痛发作过程中的这些其他伤害性信号传导途径。为了防止 CGRP 通路的激活，CGRP 受体将被单克隆抗体 erenumab 阻断。该项目由两个子项目组成。第一个子项目是在接受 erenumab 治疗的患者中使用 levcromakalim 进行安慰剂对照激发研究。根据所提出的病理生理学模型，由 levcromakalim 引发的偏头痛发作应该绕过 CGRP 受体的阻断。其他神经肽对 KATP 通道的激活可以解释为什么患者在接受 erenumab 治疗后仍然会频繁发生偏头痛。第二个子项目研究 erenumab 治疗下 PACAP-38、肾上腺髓质素和胰淀素浓度的变化。 CGRP 受体的阻断可能导致这些伤害性信号通路的代偿性上调。另一方面，如果这些途径​​真正独立，则预计不会发生相关变化。 对替代炎症信号通路的研究对于解释 CGRP 靶向治疗的治疗反应的个体差异至关重要。剖析这些分子机制将有助于确定预防偏头痛的新治疗方法。