Neuro Inflammation in Migraine, From Pathogenesis to Treatment

Migraine has been known as the first cause of disability in under 50s and affects approximately 11% of the adults in the world. Emerging evidence has focused on neurogenic inflammation theory in migraine pathogenesis which involves the release of pro-inflammatory substances that lead to activation and sensitization of peripheral nociceptors. The sensory fibers to the intracranial vasculature have their origin in the trigeminal ganglion that store calcitonin gene-related peptide (CGRP), amylin, substance P (SP), Nitric oxide (NO), neurokininA and B, pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), dynorphine, and nociception. Released peptides such as CGRP binds to the CGRP receptor on the smooth muscle cells causing a vasodilatory response with increase in the meningeal blood flow in the dural vasculature. Therefore, the augmentation of neurotransmitters CGRP, SP, PACAP, and VIP which activates and provokes mast cells release, interacts with blood vessels, neurons, and immune cells, generating inflammation by provokingvasodilation, extravasation, and glial cell activation with the production of pro-inflammatory IL-1 family members: All these activities can trigger headache. Further, there are several studies reporting augmented plasma pro-inflammatory factors including CRP, ILse.g. IL-1 and IL-6 and TNF-α in migraineurs. Also in different studies increased levels of NO, CGRP, PACAP, TNF-α and IL-1β were observed in the CSF and plasma samples of migraineurs. NO, CGRP and PACAP are among the most studied factors in migraine pathogenesisand recent studies have emphasized on new antimigraine drugs that could combat inflammatory state. These drugs certainly interfere with signaling pathways of CGRP, a vasodilatory neuropeptide expressed in the cranial sensory nerves and PACAP, a parasympatheticvasodilator peptide that is linked to cranial autonomic symptoms in migraine. To date, 4 monoclonal antibodies have been developed for migraine prophylaxis that act on the CGRP pathway. Erenumab, fremanezumab and galcanezumab were approved by the FDA for migraineprevention. There is also ongoing development of therapeutic approaches targeting both PACAP and the PAC1 receptor with a current emphasize on PACAPrelated PACAPrelated antibodies development. Although preliminary data propose that targeting PAC1 receptors might be most effective, it is also suggested targeting VPAC1 and VPAC2 receptors may still be of clinical benefit