Future targets for migraine treatment beyond CGRP

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.

Migraine Treatment: Towards New Pharmacological Targets

“…Despite the highly variable nature of trigger factors, all potentially affecting the CNS, they converge to activate the trigemino-vascular system through mechanisms that remain unclear. Over the past few decades, therapeutic strategies have progressively shifted away from CNS mechanisms of migraine towards the identification of peripheral targets [190]. Among these, CGRP, linking central trigemino-cervical system activation with peripheral processes, like mast cell degranulation and dilation of meningeal arteries, has been identified as the major contributor to migraine pain [191].…”

Migraine and Its Treatment from the Medicinal Chemistry Perspective

“…42 Other research on the pathophysiology of migraine considered increases of the neuropeptide calcitonin gene (CGRP) level in the blood. 43 CGRP is a peptide that has receptors throughout the trigeminovascular system and whose circulating level increases during migraine attacks, as seen in clinical research. 26 While the level of CGRP increases in the headache phase, stimulation occurs throughout the trigeminovascular system as a result of the increase in inflammatory mediators such as substance P and vasoinhibitory peptide.…”

“…In 1991, sumatriptan was introduced by Humphrey and colleagues as a first-line treatment in combination with NSAIDs such as ibuprofen . Other research on the pathophysiology of migraine considered increases of the neuropeptide calcitonin gene (CGRP) level in the blood . CGRP is a peptide that has receptors throughout the trigemino­vascular system and whose circulating level increases during migraine attacks, as seen in clinical research .…”

“…48 Longterm stimulation of the trigeminovascular system and hyperexcitability of trigeminal neurons cause the nociceptive pain threshold to decrease and the pain to turn into chronic headache. 43 Pituitary adenylate cyclase-activating polypeptide (PACAP) and pituitary adenylate cyclase-activating polypeptide type 1 (PAC1) receptors are potential targets that are expressed in the trigeminovascular system and may cause migraine attacks. Therefore, PACAP ligands may be promising for the treatment of migraine.…”

The history and rationale of the development of new drugs for migraine treatment

“…New molecular targets for the treatment of migraine include drugs of several classes, such as metabotropic receptors such as pituitary adenylate cyclase-activating polypeptide (PACAP-27, PACAP-38), vasoactive intestinal peptide (VIP), amylin, adrenomedullin; intracellular targets such as nitric oxide (NO), phosphodiesterase-3 (PPDE-5), phosphodiesterase-5 (PPDE-5); ion channels such as potassium channels, calcium channels, transient receptor potential (TRP) channels, acid-sensing insensitive cation channels (ASICS), and mechanosensitive Piezo channels. 111,112 Whether their potential as targets will be confirmed remains to be proven.…”