Experimental and Clinical Investigation of Cytokines in Migraine: A Narrative Review

Abstract

The role of neuroinflammation in the pathophysiology of migraines is increasingly being recognized, and cytokines, which are important endogenous substances involved in immune and inflammatory responses, have also received attention. This review examines the current literature on neuroinflammation in the pathogenesis of migraine. Elevated TNF-α, IL-1β, and IL-6 levels have been identified in non-invasive mouse models with cortical spreading depolarization (CSD). Various mouse models to induce migraine attack-like symptoms also demonstrated elevated inflammatory cytokines and findings suggesting differences between episodic and chronic migraines and between males and females. While studies on human blood during migraine attacks have reported no change in TNF-α levels and often inconsistent results for IL-1β and IL-6 levels, serial analysis of cytokines in jugular venous blood during migraine attacks revealed consistently increased IL-1β, IL-6, and TNF-α. In a study on the interictal period, researchers reported higher levels of TNF-α and IL-6 compared to controls and no change regarding IL-1β levels. Saliva-based tests suggest that IL-1β might be useful in discriminating against migraine. Patients with migraine may benefit from a cytokine perspective on the pathogenesis of migraine, as there have been several encouraging reports suggesting new therapeutic avenues.

Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study

“…Immunomodulatory effects of HMGCR inhibitors may suppress the production of inflammatory mediators and cytokines, and mitigate inflammatory responses [ 31 – 33 ]. These effects may be particularly relevant, as it has been found that patients with chronic migraines often have elevated levels of certain inflammatory markers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), which may suggest an underlying systemic inflammatory state, and activation of the trigeminal vascular system leads to a cascade of inflammatory responses, causing neurogenic inflammation, resulting in the sensitization of peripheral and central pain pathways, potentially triggering a migraine attack [ 34 – 37 ]. Moreover, HMGCR inhibitors' neuroprotective effects, including the reduction of oxidative stress, might contribute to migraine prevention [ 38 – 40 ].…”

Causal association between systemic lupus erythematosus and the risk of migraine: A Mendelian randomization study

“…Elevated plasma level of TNF‐α has also been seen in migraineurs and may contribute to the pathophysiology of migraine through several mechanisms, including increasing inflammatory reactions, sensitizing trigeminal ganglia, and activating the transcription of calcitonin gene‐related peptide (CGRP) (Durham, 2006 ; Fidan et al., 2006 ; Franceschini et al., 2013 ; Yücel et al., 2016 ). TNF‐α, trigeminal ganglia, and CGRP have been reported to be involved in the mechanism of migraine with aura (Shibata et al., 2023 ; Yamanaka et al., 2023 ). Therefore, it is possible that aCL and β2GPI contribute to migraine with aura via TNF‐α‐mediated pathways.…”

Evaluation of Dermatological and Neurological Aspects of the Relationship between Rosacea and Headaches

“…They stimulate vasodilation, inflammation, and heightened vascular permeability [ 24 , 33 ]. In patients with migraines, an increase in IL-17 and MMP activity has been detected, independent of aura [ 34 , 35 ]. These potential mechanisms, particularly the varying levels of mast cell release in different types of rosacea, may lead to variations in headache types.…”