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Abstract：
OBJECTIVE: Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years.
METHODS: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope.
RESULTS: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results.
CONCLUSIONS: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.
METHODS: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope.
RESULTS: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results.
CONCLUSIONS: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.
摘要：
目的：偏头痛是一种复杂且致残的神经系统疾病。近年来见证了这种疾病的新型治疗方法的发展和出现，即那些靶向降钙素基因相关肽（CGRP）。然而,对于那些对当前疗法无反应的患者,仍然需要进一步的治疗.近年来，靶向垂体腺苷酸环化酶激活多肽（PACAP）作为原发性头痛疾病的可能治疗策略引起了人们的兴趣。
方法：这篇综述将总结我们迄今为止对PACAP的了解：它的表达，受体,在偏头痛和丛集性头痛生物学中的作用，从偏头痛的临床前和临床模型中获得的见解，和治疗范围。
结果：PACAP与血管活性肠多肽（VIP）具有同源性，是与CGRP和VIP一起的几种血管活性神经肽之一，这与偏头痛神经生物学有关。PACAP在偏头痛病理生理学的关注领域中广泛表达，比如丘脑，三叉神经尾核,和蝶腭神经节.临床前证据表明PACAP在三叉神经血管致敏中的作用，而临床证据显示偏头痛中PACAP的发作性释放和易感个体中PACAP的静脉输注触发发作。PACAP通过其与不同的G蛋白偶联受体的结合导致硬脑膜血管舒张和继发性中枢现象。和通过环磷酸腺苷（cAMP）和磷酸激酶C（PKC）的细胞内下游效应。已经使用针对PACAP和PAC1受体开发的单克隆抗体探索了靶向PACAP作为头痛的治疗策略。初步取得积极成果。
结论：未来的临床试验对于使用PACAP靶向疗法治疗偏头痛和丛集性头痛的新治疗方法具有相当大的希望。
方法：这篇综述将总结我们迄今为止对PACAP的了解：它的表达，受体,在偏头痛和丛集性头痛生物学中的作用，从偏头痛的临床前和临床模型中获得的见解，和治疗范围。
结果：PACAP与血管活性肠多肽（VIP）具有同源性，是与CGRP和VIP一起的几种血管活性神经肽之一，这与偏头痛神经生物学有关。PACAP在偏头痛病理生理学的关注领域中广泛表达，比如丘脑，三叉神经尾核,和蝶腭神经节.临床前证据表明PACAP在三叉神经血管致敏中的作用，而临床证据显示偏头痛中PACAP的发作性释放和易感个体中PACAP的静脉输注触发发作。PACAP通过其与不同的G蛋白偶联受体的结合导致硬脑膜血管舒张和继发性中枢现象。和通过环磷酸腺苷（cAMP）和磷酸激酶C（PKC）的细胞内下游效应。已经使用针对PACAP和PAC1受体开发的单克隆抗体探索了靶向PACAP作为头痛的治疗策略。初步取得积极成果。
结论：未来的临床试验对于使用PACAP靶向疗法治疗偏头痛和丛集性头痛的新治疗方法具有相当大的希望。
