CGRP-Based Migraine Therapeutics: How Might They Work, Why So Safe, and What Next?
CGRP-Based Migraine Therapeutics: How Might They Work, Why So Safe, and What Next?
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DOI：
10.1021/acsptsci.8b00036
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发表时间：
2019-02-08
影响因子：
--
通讯作者：
Russo, Andrew F.
中科院分区：
文献类型：
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作者：
Russo, Andrew F.
偏头痛是一种使人衰弱的神经系统疾病，涉及神经肽降钙素基因相关肽（CGRP）。一个令人兴奋的发展是最近FDA批准了第一种用于预防偏头痛的CGRP靶向药物。然而，尽管有这种功效，还有一些基本的问题没有回答，例如CGRP在偏头痛中的作用部位和作用方式。临床前数据表明CGRP通过外周和中枢机制起作用。外周部位的相关性通过CGRP阻断抗体的临床功效而突出，即使它们不明显地穿过血脑屏障。最有可能的作用部位是硬脑膜和三叉神经节内。此外，由于CGRP是最有效的血管舒张肽，因此忽略硬脑膜中的血管周围作用是愚蠢的。最终，阻断CGRP或其受体的结果是降低外周神经敏化。其有效性背后的问题是，为什么这些抗体迄今为止具有如此优异的安全性。这可能是由于第二个CGRP受体的存在和大量肽的囊泡释放。最后，尽管这些药物有希望，但仍存在未满足的差距，因为它们并不适用于所有患者;那么下一步呢？我们可以期待在几个方面取得进展，包括可能有助于开发中枢作用拮抗剂的CGRP受体结构，整合其他疗法的组合治疗，以及开发靶向其他神经肽的药物。对于CGRP和偏头痛领域来说，这确实是一个令人兴奋的时刻，更多的发现即将出现。
Migraine is a debilitating neurological condition that involves the neuropeptide calcitonin gene-related peptide (CGRP). An exciting development is the recent FDA approval of the first in an emerging class of CGRP-targeted drugs designed to prevent migraine. Yet despite this efficacy, there are some fundamental unanswered questions, such as where and how CGRP works in migraine. Preclinical data suggest that CGRP acts via both peripheral and central mechanisms. The relevance of peripheral sites is highlighted by the clinical efficacy of CGRP-blocking antibodies, even though they do not appreciably cross the blood-brain barrier. The most likely sites of action are within the dura and trigeminal ganglia. Furthermore, it would be foolish to ignore perivascular actions in the dura since CGRP is the most potent vasodilatory peptide. Ultimately, the consequence of blocking CGRP or its receptor is reduced peripheral neural sensitization. Underlying their efficacy is the question of why the antibodies have such an excellent safety profile so far. This may be due to the presence of a second CGRP receptor and vesicular release of a large bolus of peptides. Finally, despite the promise of these drugs, there are unmet gaps because they do not work for all patients; so what next? We can expect advances on several fronts, including CGRP receptor structures that may help the development of centrally acting antagonists, combinatorial treatments that integrate other therapies, and development of drugs that target other neuropeptides. This is truly an exciting time for CGRP and the migraine field with many more discoveries on the horizon.