Non-neuronal targets for migraine therapy

Migraine is a highly prevalent and severe neurological condition characterized by disabling headache attacks accompanied by other neurological symptoms. Its pathophysiology involves activation of the trigeminovascular system, cortical spreading depolarization, and dysregulation of brainstem and diencephalic nuclei. Although most studies have focussed mainly on the role of neurons, there is mounting evidence that non-neuronal cells could also participate in migraine pathophysiology and could represent targets for current and future therapies. As reviewed in this manuscript, preclinical evidence links astrocytes, microglia and satellite glial cells with cortical spreading depolarization, trigeminovascular activation, and the development of orofacial allodynia, processes that are central to migraine. These cells could be potential targets for calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) therapies. Schwann cells have been less studied, but existing data suggest they could be targeted by anti-CGRP treatments. Macrophages respond to CGRP, contribute to cortical spreading depolarization and orofacial mechanical allodynia, and may be modulated to enhance an anti-inflammatory environment. Mast cells express receptors for CGRP and other relevant neuropeptides, and have gained attention through the development of monoclonal antibodies against their protease-activated receptor 2 (PAR2), currently in phase 2 clinical trials. Further studies are needed to better elucidate the molecular complexity of non-neuronal cells and their role in migraine, but future approaches using adeno-associated viral vectors, nanoparticles, and cell replacement strategies could enable the development of innovative anti-migraine therapies.