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This blog post has been re-posted from theSpringeropen博客。

Migraine is the most common neurological disorder, afflicting 10-15% of adults worldwide. Because migraines rank amongst the most debilitating conditions, the annual cost and public health burden are substantial.

偏头痛的特征主要是严重头痛的攻击，伴随着诸如声音或光线引起的恶心，呕吐和不适之类的症状。它们可以是情节性的或慢性的，定义为每月头痛少或超过15天。

Despite better understanding of the underlying mechanisms of migraine, significant gaps remain in the identification of signaling pathways and specific biomarkers. Nevertheless, a likely breakthrough in treatment options seems to be in the horizon.

偏头痛的人类模型

For the last 9 years I have done research at the Danish Headache Center (DHC) in Copenhagen, Denmark, an institution that has for more than 30 years been a world leader in the research of migraine mechanisms. A central part of this endeavor is the use of the experimental human migraine model, where disease mechanisms are dissected by experimentally inducing migraine attacks in humans.

这些研究已经确定，神经递质（例如降钙素基因相关肽（CGRP）和垂体腺苷酸环化酶激活多肽（PACAP））可以触发与大脑血管扩张有关的偏头痛攻击。在这种情况下，PACAP38已成为涉及偏头痛和簇头痛的关键信号分子。此外，脑成像研究的发现表明，PACAP38输注后偏头痛患者的神经元和血管变化。

一种新颖的偏头痛特异性药物靶标

PACAP38 has emerged as a key signaling molecule implicated in migraine and possibly also in cluster headache.

PACAP38 is a powerful vasodilator and potent trigger of migraine attacks. It belongs to the glucagon/secretin superfamily of peptides together with vasoactive intestinal polypeptide (VIP). Both of these peptides activate VPAC₁和VPAC₂受体同样，但只有PACAP38激活PAC₁receptor.

但是，有趣的是，VIP诱导血管舒张，但不会引起人类偏头痛的攻击。因此，PACAP38的偏头痛活动可能是由PAC引起的₁receptor activation. For that reason it is possible that an antagonist selective for the PAC1 receptor could be effective in the treatment of migraine.

New era in migraine treatment with antibodies

Recently, targeting the calcitonin gene-related peptide (CGRP) pathway to treat migraine is the first mechanism based and focused therapeutic option to date that is shown to be effective. Clinical data from phase II and III trials of four CGRP function-blocking monoclonal antibodies (mAbs) – antibodies made of identical immune cells – collectively show a positive effect in the preventive treatment of episodic and chronic migraine with favorable side effect profiles. The anti-CGRP mAbs are expected to act in the nervous system structures outside the blood-brain barrier but their exact site of action is yet unclear and further studies are warranted.

鉴于这一点，看到抗PAC的效果将非常有趣₁偏头痛患者的受体mAB。

In my opinion, the anti-PAC₁receptor mAbs have the potential to be more effective than anti-CGRP mAbs due to the fact that the PAC₁target is seemingly more migraine-specific. I am therefore eagerly awaiting the results of an ongoing proof of concept randomized clinical trial revealing the therapeutic potential of anti-PAC₁预防偏头痛的受体抗体。这是否会成为偏头痛治疗的另一个突破和范式变化，只有时间才能证明。