Migraine Treatment: Towards New Pharmacological Targets

Abstract

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.

Atogepant: Mechanism of action, clinical and translational science

“…Advances in preclinical and human models that allow careful control and monitoring of various end points in experimentally induced migraine and associated changes with treatments are providing evidence for other signaling pathways involved in migraine neurobiology. 25 In addition to CGRP, nitric oxide, pituitary adenylate cyclaseactivating polypeptide, and vasoactive intestinal peptide have been observed to induce migraine-like attacks in humans. 25 A recent study in a human provocation model has demonstrated that increasing cAMP with cilostazol during CGRP blockade can induce a migraine attack through CGRP-independent pathways.…”

“…25 In addition to CGRP, nitric oxide, pituitary adenylate cyclaseactivating polypeptide, and vasoactive intestinal peptide have been observed to induce migraine-like attacks in humans. 25 A recent study in a human provocation model has demonstrated that increasing cAMP with cilostazol during CGRP blockade can induce a migraine attack through CGRP-independent pathways. 26 Thus, although CGRP-targeted therapies have significantly advanced migraine treatment, patients with migraine requiring newer therapeutic modalities still exist, suggesting the need for a better understanding of the disease to explore additional mechanisms for intervention.…”

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

“…The etiology of migraines is believed to be multifactorial, involving a combination of genetic predisposition and environmental factors. Neurovascular reactions, triggered by cyclic changes in the central nervous system or specific triggers, contribute to the development of migraines [ 281 ]. While some individuals may experience only isolated episodes, a genetic threshold likely plays a role in the tendency for recurrent attacks [ 280 ].…”

From CGRP to PACAP: Unraveling the Next Chapter in Migraine Treatment

“…VIP has also been implicated in the pathophysiology of migraine [111]. The similarities between PACAP and VIP in their roles in migraine include: PACAP and VIP are released in conjunction with migraine and cluster headache attacks [112]; PACAP and VIP are potent vasodilators and can cause migraine-like attacks when infused into people [113]; A 2-hour infusion of VIP caused migraine attacks, indicating that VIP plays a significant role in the pathophysiology of migraines and intravenous administration of PACAP-38 caused headaches in all healthy subjects and migraine-like attacks in 58% of patients with a history of migraine without aura [15,35]; PACAP and VIP receptors are preferentially coupled to Gαs, leading to activation of AC, subsequent cAMP production, and activation of PKA [114]; PKA may in turn activate ERKs [115]; PACAP and VIP receptor-mediated signaling pathways are shown to share activities, including vasodilation, neurogenic inflammation, and nociception in rodents [116] ; PACAP and VIP receptors provide a rich set of targets to complement and augment the current CGRP-based migraine therapeutics; VPAC1 receptors play a dominant role in PACAP-induced vasorelaxation in female mice [117].…”