Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings

Abstract

In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.

Keywords: CGRP; biofluids; endocannabinoid system; inflammation; migraine.

Figure 1

Mechanisms underlying migraine pathophysiology: Reciprocal interactions among the systems and pathways whose components are altered in migraine patients and potential molecular interactions within the neuropeptides (i.e., CGRP)–inflammation–ECS in neuronal and non-neuronal cells. Red arrow: increase; green arrow: decrease; BDNF: brain-derived neurotrophic factor; cAMP: cyclic AMP; cGMP: cyclic GMP; CGRP: calcitonin gene-related peptide; COX-2: cyclooxygenase-2; CREB: cyclic AMP response element-binding protein; ECS: endocannabinoid system; E/L: endocannabinoids and related lipids; Glut: glutamatergic signaling; IL-6: interleukin 6; KP: kynurenic pathway; MAPKs: mitogen-activated protein kinases; MMP-9: matrix metallopeptidase 9; NF-kB: nuclear factor kappa B; NGF: nerve growth factor; NO: nitric oxide; PACAP: pituitary adenylate-cyclase-activating polypeptide; PGE2: prostaglandin E2; SP: substance P; TNF-α: tumor necrosis factor-alpha.