One of the hypotheses about the origin of headache and migraine, completely related to oxidative stress, is the neurogenic inflammation of the “hard mater” presented by Moskowitz et al. According to this model, the central stimulation in the nerve endings of the trigeminal causes an antidromic release of substance P, a peptide related to the calcitonin gene (CGRP) and neurokinin A, which increases the permeability of the vascular walls and dilates them with a possible participation of nitric oxide (NO) and improves the action of factors derived from blood, such as histamine and serotonin. This leads to inflammatory reactions and edema of blood vessels, that is, aseptic inflammation of the arteries.
Considerable circumstantial evidence suggests that neuroinflammation in the intracranial meninges is the key element that results in sensitization of meningeal trigeminal nociceptors to migraine (“Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect”. Theoharides TC, Endocrinology 1995), (“The Role of Mast Cells in Migraine Pathophysiology”; Theoharides TC, Brain Res Brain Res Rev. 2005), Dalkara T, Zervas NT, Moskowitz MA (2006). (“From spreading depression to the trigeminovascular system”. Dalkara T. Et al .; Neurol Sci 2006), (“Endogenous mechanisms underlying the activation and sensitization of meningeal nociceptors: the role of immuno-vascular interactions and cortical spreading depression”. Levi D et al., Curr Pain Headache Rep 2012).
It is believed that in this state of persistent pain there is a cascade of events such as neuropeptide release, vasodilation, extravasation of plasma proteins and degranulation of mast cells that form the basic characteristics of the sterile inflammatory state (“Release of vasoactive peptides in the extracerebral circulation. of man and the cat during activation of the trigeminovascular system”. Goadsby PJ et al., Ann Neurol 1988).
Cytokines are important mediators of anti-inflammatory immune pathways and their receptors are widely expressed in the central nervous system by all cell types, including neurons, indicating that they can act on neuronal receptors.
It is now considered that cytokines are the mediators of pain in neurovascular inflammation. Cytokines can be a cause of migraine pain: in fact, a high level of chemokines could stimulate trigeminal nerve activation, the release of vasoactive peptides or other biochemical mediators, such as nitric oxide, and cause inflammation (“Cytokines and migraine: increase of IL-5 and IL-4 plasma levels”. Munno I et al., Headache 1998. “Pathogenesis of the migraine attack”. Spierings EL et al., Clin J Pain 2003).
Increased levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) have recently been reported in patients with migraine compared with control (“Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessmentictally”;(Sarchielli P. et al., Headache 2006).
“Effects of tumor necrosis factor-β (TNF-β) 252A> G polymorphism on the development of migraine”: A meta-analysis. Liu R, Ma M et al .; PLoS One 2014″.
Also, high levels of C-reactive protein (CRP) in blood have been proven to be related to migraine: “C-reactive protein and migraine. Facts or speculations?”; Lippi. et al Clin Chem Lab Med; 2014″.
Increased CRP values have been associated with migraine and have been considered as a marker of evidence of inflammation in patients with migraine (“Bilirubin Serum and Their Association With C-Reactive Protein in Patients With Migraine”; You-Fan Peng et al .; Clinical Laboratory Analysis 2016″ and “A relationship between absolute monocyte count and C-reactive protein in patients with migraine undergoing no pharmacological therapy”. Peng YF et al., Clin Chem Lab Med 2016).
Several cytokines such as IL-6, TNF and IL-10 are involved in the pathogenesis of migraine attacks, in which these inflammatory cytokines can promote the sensitization of nerve endings during recurrent attacks of migraine (“Association of serum levels” of intercellular adhesion molecule-1 and interleukin-6 with migraine”. Wang F et al., Neurol Sci 2015).
The enzyme cyclooxygenase (COX-2) is responsible for pain and inflammation, and is related to those suffering from migraine: “Our findings suggest that the genotype COX-2-765 G + could facilitate the development of migraine disease” (“Cox-2 gene variants in migraine”; Dasdemir S et al., Gene. 2013.
Plasma levels of COX-2 and visfatin in the headache attack period group were significantly higher than in the headache-free period group and the control group. In conclusion: COX-2 and visfatin participated in the pathogenesis of migraine headaches (“Plasma Levels of Cyclooxygenase-2 (COX-2) and Visfatin During Different Stages and Different Subtypes of Migraine Headaches”; Li C et al Med Sci Monit 2017)
Gaur et al. revealed that COX-2 inhibitors protect against brain brain damage and inflammation caused by irradiation injury (Gaur and Kumar, 2012). “This suggests that there is a relationship between the immune system and the central nervous system”.
This study (“Exercise suppresses COX-2 pro-inflammatory pathway in vestibular migraine”; Yi-Yen Lee et al., Bran Research Bulletin, 2015) demonstrated that plasma concentrations of IL-1, TNF-α, IFN-γ, IL-2, IL-6, and IL-8 were significantly higher in patients with MV compared with the control.
They concluded that “in patients with migraine, COX-2 inhibitors could have a therapeutic effect”. The combination of COX-2 inhibition and exercise intervention can work together to achieve a successful treatment strategy. Our results suggest that exercise has a therapeutic benefit in patients with migraine. After physical training, we observed suppressed proinflammatory modulators and the repression of the redox state through the inhibition of COX-2″.
Activation of helper T lymphocytes and increased levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1β, IL-2, IL-4, IL-10 and interferon-γ (IFN-γ) have been reported in migraine (Perini, F. et al “Plasma cytokine levels in migraineurs and controls”; Headache, 2005).
Nitric oxide (NO) is one of the gases produced in macrophages. It is synthesized by NO synthase (NOS). The inducible NO synthase, known as iNOS, is activated when macrophages (cells dominant in chronic inflammation) are activated by cytokines. It is considered to be a marker of inflammation.
Inappropriate stimulation of iNOS can lead to excessive production of NO, which would play a part in the pathogenesis of inflammatory vascular diseases such as migraine.
Nitric oxide (NO) and the NO donor, nitroglycerin, have been widely used as triggers for human migraine. Consequently, it has been shown that several components of the NO signaling cascade are positively regulated in patients with migraine. NO is produced endogenously in the body by NO synthase (NOS), of which there are three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Based on the accumulated evidence that endogenous NO regulation is altered in the pathogenesis of migraine, the global inhibitors and selective inhibitors of the NOS isoform have focused on the development of migraine drugs. This review highlights the evidence of the role of NO in migraine and focuses on the use of NOS inhibitors for the treatment of this disorder. In addition, we discuss other molecules within the NO signaling pathway that may be promising therapeutic targets for migraine (“Targeted Nitric Oxide Synthase Inhibitors for Migraine”; Pradhan AA et al., Neurotherapeutics, 2018).
Acute inflammatory responses induced by oxidative stress may play an important role in the pathogenesis of acute migraine pain (“Oxidative stress and DNA damage in patients with migraine”; Geyik S et al., J Headache Pain, 2016).