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Review
. 2023 Jun 28;24(1):76.
doi: 10.1186/s10194-023-01567-4.

Future targets for migraine treatment beyond CGRP

Linda Al-Hassany  1 , Deirdre M Boucherie  1 , Hannah Creeney  2 , Ruben W A van Drie  1   3 , Fatemeh Farham  4 , Silvia Favaretto  5 , Cédric Gollion  6 , Lou Grangeon  7 , Hannah Lyons  8 , Karol Marschollek  9 , Dilara Onan  10   11 , Umberto Pensato  12   13 , Emily Stanyer  2 , Marta Waliszewska-Prosół  9 , Wietse Wiels  14 , Hui Zhou Chen  2 , Faisal Mohammad Amin  15   16 ; European Headache Federation School of Advanced Studies (EHF-SAS)
Affiliations
Review

Future targets for migraine treatment beyond CGRP

Linda Al-Hassany et al. J Headache Pain. .

Abstract

Background: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine.

Findings: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results.

Conclusion: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Keywords: Adrenomedullin; Amylin; Ion channels; Migraine; Nitric oxide; Non-CGRP targets; Phosphodiesterases; Pituitary adenylate cyclase-activating polypeptide; Vasoactive intestinal polypeptide.

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Conflict of interest statement

Linda Al-Hassany, Deirdre M. Boucherie, Hannah Creeney, Ruben W.A.van Drie, Fatemeh Farham, Silvia Favaretto, Grangeon Lou, Hannah Lyons, Karol Marschollek, Dilara Onan, Umberto Pensato, Emily Stanyer, Marta Waliszewska-Prosół, Hui Zhou Chen declare no conflict of interest. Cédric Gollion reports speaker fees from Teva, Novartis, Lundbeck and Lilly. Wietse Wiels declares to have received an FWO Vlaanderen Fundamental Research scholarship. Faisal Mohammad Amin has received Honoraria or personal fees from Pfizer, Teva, Novartis, Lundbeck and Eli Lilly for lecturing or participating in advisory boards; is principal investigator for phase IV trials sponsored by Novartis and by Teva; serves as president of Danish Headache Society and board member of the European Headache Federation; serves as associate editor for Acta Neurol Scand, Front Neurol, Front Res Pain, and Headache Medicine; serves as junior associate editor for Cephalalgia and Cephalalgia Reports; member of the editorial board of J Headache Pain.

Figures

Fig. 1
Fig. 1
A schematic, yet simplified, overview of (the interaction of) several CGRP-related and non-CGRP-related targets that might be of interest as future therapies in migraine. The final action of these targets is the efflux of potassium via the opening of KATP and BKCa channels. The figure was created using Biorender. Abbreviations: AC, Adenylate Cyclase; ADM, Adrenomedullin; AMP, Adenosine Monophosphate; AMY1, Amylin Receptor 1; AMY2, Amylin Receptor 2; BKCa, Big Conductance Calcium-Activated Potassium Channel; cAMP, Cyclic Adenosine Monophosphate; cGMP, Cyclic Guanosine Monophosphate; CGRP, Calcitonin Gene-Related Peptide; sGC, soluble Guanylyl Cyclase; KATP, Adenosine Triphosphate-Sensitive Potassium Channel; NO, Nitric Oxide; PAC1, Pituitary Adenylate Cyclase-Activating Polypeptide Type 1 Receptor; PACAP, Pituitary Adenylate Cyclase-Activating Polypeptide; PKA, Protein Kinase A; PKG, Protein Kinase G; PDE, phosphodiesterase; VIP, Vasoactive Intestinal Polypeptide; VPAC, Vasoactive Intestinal Polypeptide Receptor
Fig. 2
Fig. 2
Mean induction rates (with their standard deviations) of migraine attacks (irrespective of aura symptoms) of non-CGRP targets compared to placebo, as observed in placebo-controlled studies in migraine patients. PACAP38 rate is based on [57] and [20] – the latter is a head-to-head comparison study of PACAP38 and VIP (instead of placebo); PACAP27 rate is based on [60]; VIP rate is based on [20] with an active control (PACAP38) and [79, 80]. Please note that infusion duration in the study of Rahmann et al. [79] was 25 minutes, while it was two hours in the study of Pellesi et al. [80]; pramlintide rate is based on [88] which was compared to CGRP and not to placebo; adrenomedullin rate is based on [99]; nitroglycerin rate is based on [190]; cilostazol (PDE3 inhibitor) rate is based on [116]; sildenafil (PDE5 inhibitor) rate is based on [129], and levcromakalim rate is based on [137, 191]. Please note that [191] only included migraine with aura patients
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