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Pituitary adenylate cyclase-activating polypeptide signalling as a therapeutic target in migraine

Nature Reviews Neurology volume 20, pages 660–670 (2024)Cite this article

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Abstract

Migraine is a disabling neurological disorder that affects more than one billion people worldwide. The clinical presentation is characterized by recurrent headache attacks, which are often accompanied by photophobia, phonophobia, nausea and vomiting. Although the pathogenesis of migraine remains incompletely understood, mounting evidence suggests that specific signalling molecules are involved in the initiation and modulation of migraine attacks. These signalling molecules include pituitary adenylate cyclase-activating polypeptide (PACAP), a vasoactive peptide that is known to induce migraine attacks when administered by intravenous infusion to people with migraine. Discoveries linking PACAP to migraine pathogenesis have led to the development of drugs that target PACAP signalling, and a phase II trial has provided evidence that a monoclonal antibody against PACAP is effective for migraine prevention. In this Review, we explore the molecular and cellular mechanisms of PACAP signalling, shedding light on its role in the trigeminovascular system and migraine pathogenesis. We then discuss emerging therapeutic strategies that target PACAP signalling for the treatment of migraine and consider the research needed to translate the current knowledge into a treatment for migraine in the clinic.

Key points

  • Pituitary adenylate cyclase-activating polypeptide (PACAP) signalling has been identified as an important pathogenic contributor to migraine, supported by evidence from both animal and human studies.

  • PACAP causes vasodilation and influences immune cell recruitment and activation, which are processes implicated in the pathophysiology of migraine.

  • Intravenous infusion of PACAP can induce migraine attacks in humans, highlighting its direct role in migraine pathogenesis.

  • A monoclonal antibody against PACAP signalling has shown promise in a phase II trial for migraine prevention, indicating potential therapeutic benefits.

  • The complexity of the role that PACAP has in migraine is underscored by its interaction with multiple receptors and the trigeminovascular system; further research is needed to fully understand the therapeutic potential of targeting PACAP signalling.

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Fig. 1: Splice variants of the PAC1 receptor.
Fig. 2: Intracellular signalling pathways activated by pituitary adenylate cyclase-activating polypeptide.
Fig. 3: Hypothesized cellular effects of pituitary adenylate cyclase-activating polypeptide vary across different cell types in migraine pathogenesis.
Fig. 4: Sites of pituitary adenylate cyclase-activating polypeptide action within the trigeminovascular system.
Fig. 5: The history of pituitary adenylate cyclase-activating polypeptide research.

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Authors and Affiliations

  1. Department of Neurology, Danish Headache Center, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark

    Håkan Ashina, Rune H. Christensen & Messoud Ashina

  2. Translational Research Center, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark

    Håkan Ashina & Rune H. Christensen

  3. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Rune H. Christensen & Messoud Ashina

  4. Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand

    Debbie L. Hay

  5. Center for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St Louis, St Louis, MO, USA

    Amynah A. Pradhan

  6. Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Jan Hoffmann

  7. Department of Anatomy, Centre for Neuroscience, University of Pécs Medical School, Pécs, Hungary

    Dora Reglodi

  8. Department of Molecular Physiology and Biophysics, University of Iowa, Veterans Affairs Healthcare System, Iowa City, IA, USA

    Andrew F. Russo

  9. Department of Neurology, University of Iowa, Veterans Affairs Healthcare System, Iowa City, IA, USA

    Andrew F. Russo

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Contributions

H.A., R.H.C. and M.A. researched data for the article and contributed to writing of the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Messoud Ashina.

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Competing interests

H.A. has received personal fees from AbbVie, Lundbeck, Pfizer and Teva that are unrelated to this manuscript. D.L.H. has received research support from AbbVie and Pfizer and has acted as an adviser, speaker or consultant for AbbVie, Amgen, Eli Lilly, Merck, Nxera Pharma and Teva. D.L.H. also receives funding from the NIH (RF1 NS113839). The contents of this manuscript do not represent the views of the US Government. At the time of drafting and submitting this manuscript, J.H. was employed as an academic researcher at King’s College London, UK. Since 1st May 2024, he has been employed by H. Lundbeck A/S; since this time, he has approved the manuscript but has made no changes. Prior to his employment at H. Lundbeck A/S, J.H. received honoraria for consulting activities and/or serving on advisory boards and/or as a speaker from AbbVie, Allergan, Autonomic Technologies, Cannovex, Chordate Medical, Eli Lilly, Hormosan Pharma, H. Lundbeck A/S, MD-Horizonte, Novartis, Pfizer, Sanofi and Teva. He has received personal fees for Medico-Legal work and from NEJM Journal Watch, Oxford University Press, Quintessence Publishing, Sage Publishing and Springer Healthcare. He holds stock options from Chordate Medical. He has also received research grants from Bristol Myers Squibb, the National Institute for Health and Care Research (NIHR), the Medical Research Council (MRC), the International Headache Society (IHS) and the Migraine Trust. He serves or has served as Associate Editor for Cephalalgia, Cephalalgia Reports, Frontiers in Pain Research, Journal of Headache and Facial Pain and Journal of Oral & Facial Pain. He has been an elected member of the Board of Trustees as well as the Science and Research Committee of the IHS as well as a Council Member and Treasurer of the British Association for the Study of Headache. A.F.R. has received personal fees from AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, Paragon and Schedule One Pharmaceuticals unrelated to this manuscript. A.F.R. receives funding from the NIH (R01 NS075599, RF1 NS113839 and R01 NS129573), Veterans Administration (IO1 RX003523) and Pfizer. The contents of the manuscript do not represent the views of the Veterans Administration or the US Government. M.A. has received personal fees from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Escient, GlaxoSmithKline, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals unrelated to this manuscript. M.A. also serves as an associate editor of Brain and The Journal of Headache and Pain. The other authors declare no competing interests.

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Ashina, H., Christensen, R.H., Hay, D.L. et al. Pituitary adenylate cyclase-activating polypeptide signalling as a therapeutic target in migraine. Nat Rev Neurol 20, 660–670 (2024). https://doi.org/10.1038/s41582-024-01011-4

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