Migraine pathways and the identification of novel therapeutic targets

ABSTRACT

Introduction: Migraine is a chronic neurovascular disorder characterized by recurrent headache attacks associated with neurological and autonomic symptoms. The pathophysiological mechanisms of the disease are extremely complex, involving hypothalamic and trigeminovascular activation, cortical spreading depression, release of pro-inflammatory peptides, peripheral and central sensitization. The underlying cellular and molecular mechanisms have been scarcely investigated. Recently, genetic studies have suggested that different metabolic pathways could be involved in the pathogenesis of migraine.

Areas covered: This review focuses on cellular and molecular mechanisms involved in migraine, suggesting a role for circadian clocks, ion channels, synaptic plasticity, vascular factors, ion metal homeostasis, and impaired glucose metabolism in the pathogenesis of the disease. Accordingly, the article proposes new therapeutic targets that may be of particular relevance for disease prevention.

Expert opinion: Several complex molecular mechanisms are involved in setting the genetic threshold for migraine and the pathogenesis of headache attacks. Most promising new therapeutic targets are the modulation of hypothalamic activity and ion channels involved in pain transmission. Further studies in animals and humans are necessary to enhance the elucidation of the molecular mechanisms of migraine and open new avenues for disease prevention.

KEYWORDS:

• Migraine
• aura
• circadian clocks
• hypothalamus
• ion channels
• metal ion homeostasis
• glucose metabolism
• therapeutic target
• PACAP1-38
• TRPM8

Article Highlights

• Genetic factors are key players in positioning the threshold for migraine. Mendelian forms of migraine are very rare while the more common forms are transmitted as oligogenic or polygenic complex traits.

• Genetic studies showed that different metabolic pathways may be involved in the predisposition to the disease and in headache attacks.

• Hypothalamic activation has a significant role in the pathogenesis of the migraine attack. Further development of monoclonal antibodies that target PACAP1-38 and its receptor may be valuable in migraine therapy.

• Modulation of ion channels that are involved in pain transmission, e.g., TRESK and TRPM8, may offer new opportunities in migraine prophylaxis.

• Animal and human studies are necessary for the elucidation of the complex molecular mechanism of migraine and potential therapeutic targets.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of the authors was fully supported by 2018 research grants from the Ministero dell’Università e della Ricerca Scientifica (MIUR) of Italy, under the Project Departments of Excellence.