The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target?
The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target?
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DOI：
10.1093/brain/awac040
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发表时间：
2022-07-11
期刊：
影响因子：
14.5
通讯作者：
Kristensen, David M.
中科院分区：
文献类型：
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作者：
Ernstsen, Charlotte;Christensen, Sarah L.;Kristensen, David M.
Ernstsen等人使用体内和离体模型表明，PACAP-38引起偏头痛样变化，与CGRP无关，仅部分通过K-ATP通道。由于高达50%的偏头痛患者对CGRP靶向治疗无反应，PACAP-38拮抗作用可能代表一种替代治疗方法。降钙素基因相关肽（CGRP）拮抗药物代表了偏头痛治疗的重大进展。然而，高达50%的患者不能从抗CGRP或其受体的单克隆抗体中获益。在这里，我们测试的假设，一个密切相关的肽，垂体腺苷酸环化酶激活肽（PACAP-38），独立于CGRP的工作，因此可能代表一个新的，替代药物的目标。为了了解CGRP和PACAP介导的偏头痛的差异，我们使用了基于多次刺激和随后用von Frey细丝测量触觉敏感性反应的诱发偏头痛样疼痛的小鼠模型。将缺乏功能性CGRP受体（Ramp 1敲除）或TRPA 1通道（Trpa 1敲除）的遗传修饰小鼠与野生型小鼠中的CGRP靶向抗体和化学抑制剂一起使用（n（总数）= 299）。离体肌描记器研究用于测量小鼠颈动脉中对CGRP和PACAP-38的扩张反应。PACAP-38引起显著的超敏反应，并独立于CGRP扩张颈动脉。相反，甘油三硝酸酯诱导的超敏反应依赖于CGRP。与先前的偏头痛诱导物质三硝酸甘油、西洛他唑和左克罗卡林的结果相反，PACAP-38诱导的超敏反应仅部分通过抑制ATP敏感性钾通道起作用。使用多种偏头痛相关模型，这些发现建立了PACAP-38通路，与其他偏头痛引发通路（如CGRP和甘油三硝酸酯）不同。因此，PACAP拮抗作用可能是对CGRP拮抗药物无反应的患者特别感兴趣的新的治疗靶点。
Using in vivo and ex vivo models, Ernstsen et al. show that PACAP-38 provokes migraine-like changes independently of CGRP and only partially through K-ATP channels. Since up to 50% of migraine patients are non-responsive to CGRP-targeting therapies, PACAP-38 antagonism could represent an alternative therapeutic approach.Calcitonin gene-related peptide (CGRP)-antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP- and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-targeting antibodies and chemical inhibitors in wild-type mice (n(total) = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP-antagonizing drugs.