Role of TNF -α in the Pathogenesis of Migraine

Abstract

Background: Neurogenic neuroinflammation has a wide role in migraine pathogenesis including the transition from episodic migraine to chronic one. The seed molecule of neurogenic neuroinflammation, i.e., the TNF-α proinflammatory molecule, has gathered a lot of attention. This pleiotropic cytokine is a classical component of inflammatory soup, secreted by the microglial cell, and promotes a wide range of inflammatory reactions.

Aim: In this review, we aimed to provide a culminating and comprehending glimpse into the TNF-α in association with the migraine.

Method: A systematic literature survey method with a mixture of keywords was utilized to grasp the different elements that represent the association between TNF-α and migraine. Discussion. Highlighted the probable involvement of the TNF-α with migraine, the complexity of the matter such as activation of NF-KB signaling cascade, autoactivation, sensitization, and increased likelihood of transition cannot be neglected. Being TNF-α as a core node, it becomes the factor for linking diseases such as chronic inflammatory disorders, including COVID-19, and also interaction with other genes to develop severe conditions.

Conclusion: To this end, TNF-α plays a critical role in chronification, and inhibiting its signaling would likely be a crucial strategy for migraine therapy.

Figure 1

Systematic representation of literature survey according to PRISMA criteria.

Figure 2

OMIM radial PheneGene graphs depicts the complex interaction of the TNF-α with different gene and are responsible for the diverse number of diseases and also with the migraine (highlighted with star) (OMIM-Online Mendelian Inheritance in Man (https://www.omim.org/)).

Figure 3

(a) Brain atlas has enlightened that TNF-α has a high expression in the various part of same including white matter, medulla oblongata, and pons (brain tissue expression of TNF-Summary-The Human Protein Atlas (https://www.proteinatlas.org/ENSG00000232810-TNF/brain)). (b) Microarray Data Allen Brain Atlas: human brain (brain-map.org. (c) −308G > A allele worldwide frequency in different population including African (AFR), American (AMR), EAS (East Asia), EUR (Europe), and SAS (South Asia) (Ensembl genome browser 105 (https://asia.ensembl.org/index.html)).

Figure 4

(a) The cycle begins with the binding of CGRP to its receptor, the CGRPR, which activates PKA (protein kinase A), which then phosphorylates the MAPK (mitogen activating protein kinase). When MAPK is phosphorylated, it causes p38 expression to increase as a result of the phosphorylation. The phosphorylated form of p38 subsequently enters the nucleus, where it stimulates the production of inflammatory genes such as TNF-α, protease. (b) After enhanced expression of protease, cleavage of mTNF-α is cleaved which after then binds with the TNFR1. Cascade of signal protein activation occurs after binding of sTNF-α to its TNFR1 which leads to the activation of IKK. IKK is responsible for the activation of NF-KB and activated form of protein enters into the nucleus and cause enhanced inflammation reaction.

Figure 5

Flow diagram depicts how migrainous brain is triggered by slow propagating wave (2–5 mm·min⁻¹) of all cortical neuronal and astrocyte depolarization leads to release of vasoactive product such as CGRP and neurotransmitter (glutamate). Microglial activation is caused by both CGRP and glutamate and stimulates the release of TNF-α which is the prime focus of inflammation. TNF-α also autostimulates and causes positive loop activation and is responsible for the sensitization of nociceptors, and this continuous stimulation will become a risk factor for the transition of episodic to chronic headache.