International Journal of Molecular Sciences

Editorial

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6 pages, 220 KiB

Open AccessEditorial

Molecular Research on Migraine: From Pathogenesis to Treatment

by Antonino Tuttolomondo and Irene Simonetta

Int. J. Mol. Sci. 2023, 24(10), 8681; https://doi.org/10.3390/ijms24108681 - 12 May 2023

Cited by 1 | Viewed by 920

Abstract

Migraine is a common, multifactorial, disabling, recurrent, hereditary, neurovascular headache disorder [...] Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

Research

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9 pages, 289 KiB

Open AccessArticle

Polymorphisms of the Proinflammatory Cytokine Genes Modulate the Response to NSAIDs but Not to Triptans in Migraine Attacks

by Elisa Rubino, Andrea Marcinnò, Alberto Grassini, Elisa Maria Piella, Fabio Ferrandes, Fausto Roveta, Silvia Boschi, Aurora Cermelli, Salvatore Gallone, Lidia Savi and Innocenzo Rainero

Int. J. Mol. Sci. 2023, 24(1), 657; https://doi.org/10.3390/ijms24010657 - 30 Dec 2022

Cited by 3 | Viewed by 1293

Abstract

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a [...] Read more.

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1β, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (−308 A/G) and a lack of efficacy after NSAID administration (p < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

12 pages, 2154 KiB

Open AccessArticle

A Hypothalamic Mechanism Regulates the Duration of a Migraine Attack: Insights from Microstructural and Temporal Complexity of Cortical Functional Networks Analysis

by Camillo Porcaro, Antonio Di Renzo, Emanuele Tinelli, Vincenzo Parisi, Cherubino Di Lorenzo, Francesca Caramia, Marco Fiorelli, Giada Giuliani, Ettore Cioffi, Stefano Seri, Vittorio Di Piero, Francesco Pierelli, Giorgio Di Lorenzo and Gianluca Coppola

Int. J. Mol. Sci. 2022, 23(21), 13238; https://doi.org/10.3390/ijms232113238 - 31 Oct 2022

Cited by 5 | Viewed by 1743

Abstract

The role of the hypothalamus and the limbic system at the onset of a migraine attack has recently received significant interest. We analyzed diffusion tensor imaging (DTI) parameters of the entire hypothalamus and its subregions in 15 patients during a spontaneous migraine attack [...] Read more.

The role of the hypothalamus and the limbic system at the onset of a migraine attack has recently received significant interest. We analyzed diffusion tensor imaging (DTI) parameters of the entire hypothalamus and its subregions in 15 patients during a spontaneous migraine attack and in 20 control subjects. We also estimated the non-linear measure resting-state functional MRI BOLD signal’s complexity using Higuchi fractal dimension (FD) and correlated DTI/fMRI findings with patients’ clinical characteristics. In comparison with healthy controls, patients had significantly altered diffusivity metrics within the hypothalamus, mainly in posterior ROIs, and higher FD values in the salience network (SN). We observed a positive correlation of the hypothalamic axial diffusivity with migraine severity and FD of SN. DTI metrics of bilateral anterior hypothalamus positively correlated with the mean attack duration. Our results show plastic structural changes in the hypothalamus related to the attacks severity and the functional connectivity of the SN involved in the multidimensional neurocognitive processing of pain. Plastic changes to the hypothalamus may play a role in modulating the duration of the attack. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

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17 pages, 2026 KiB

Open AccessArticle

Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain

by Cindy Guerrero-Toro, Kseniia Koroleva, Elizaveta Ermakova, Oleg Gafurov, Polina Abushik, Pasi Tavi, Guzel Sitdikova and Rashid Giniatullin

Int. J. Mol. Sci. 2022, 23(3), 1529; https://doi.org/10.3390/ijms23031529 - 28 Jan 2022

Cited by 12 | Viewed by 3094

Abstract

The pro-nociceptive role of glutamate in the CNS in migraine pathophysiology is well established. Glutamate, released from trigeminal afferents, activates second order nociceptive neurons in the brainstem. However, the function of peripheral glutamate receptors in the trigeminovascular system suggested as the origin site [...] Read more.

The pro-nociceptive role of glutamate in the CNS in migraine pathophysiology is well established. Glutamate, released from trigeminal afferents, activates second order nociceptive neurons in the brainstem. However, the function of peripheral glutamate receptors in the trigeminovascular system suggested as the origin site for migraine pain, is less known. In the current project, we used calcium imaging and patch clamp recordings from trigeminal ganglion (TG) neurons, immunolabelling, CGRP assay and direct electrophysiological recordings from rat meningeal afferents to investigate the role of glutamate in trigeminal nociception. Glutamate, aspartate, and, to a lesser extent, NMDA under free-magnesium conditions, evoked calcium transients in a fraction of isolated TG neurons, indicating functional expression of NMDA receptors. The fraction of NMDA sensitive neurons was increased by the migraine mediator CGRP. NMDA also activated slowly desensitizing currents in 37% of TG neurons. However, neither glutamate nor NMDA changed the level of extracellular CGRP. TG neurons expressed both GluN2A and GluN2B subunits of NMDA receptors. In addition, after removal of magnesium, NMDA activated persistent spiking activity in a fraction of trigeminal nerve fibers in meninges. Thus, glutamate activates NMDA receptors in somas of TG neurons and their meningeal nerve terminals in magnesium-dependent manner. These findings suggest that peripherally released glutamate can promote excitation of meningeal afferents implicated in generation of migraine pain in conditions of inherited or acquired reduced magnesium blockage of NMDA channels and support the usage of magnesium supplements in migraine. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

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Review

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11 pages, 247 KiB

Open AccessReview

Orofacial Migraine or Neurovascular Orofacial Pain from Pathogenesis to Treatment

by Yair Sharav, Yaron Haviv and Rafael Benoliel

Int. J. Mol. Sci. 2023, 24(3), 2456; https://doi.org/10.3390/ijms24032456 - 27 Jan 2023

Cited by 4 | Viewed by 2447

Abstract

The purpose of the present study is to examine possible differences between orofacial migraine (OFM) and neurovascular orofacial pain (NVOP). Facial presentations of primary headache are comparable to primary headache disorders; but occurring in the V2 or V3 dermatomes of the trigeminal nerve. [...] Read more.

The purpose of the present study is to examine possible differences between orofacial migraine (OFM) and neurovascular orofacial pain (NVOP). Facial presentations of primary headache are comparable to primary headache disorders; but occurring in the V2 or V3 dermatomes of the trigeminal nerve. These were classified and recently published in the International Classification of Orofacial Pain, 1st edition (ICOP). A category in this classification is “orofacial pains resembling presentations of primary headaches,” which encompasses OFM and NVOP. The differences between NVOP and OFM are subtle, and their response to therapy may be similar. While classified under two separate entities, they contain many features in common, suggesting a possible overlap between the two. Consequently, their separation into two entities warrants further investigations. We describe OFM and NVOP, and their pathophysiology is discussed. The similarities and segregating clinical signs and symptoms are analyzed, and the possibility of unifying the two entities is debated. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

40 pages, 832 KiB

Open AccessReview

New Insights on Metabolic and Genetic Basis of Migraine: Novel Impact on Management and Therapeutical Approach

by Irene Simonetta, Renata Riolo, Federica Todaro and Antonino Tuttolomondo

Int. J. Mol. Sci. 2022, 23(6), 3018; https://doi.org/10.3390/ijms23063018 - 11 Mar 2022

Cited by 4 | Viewed by 4091

Abstract

Migraine is a hereditary disease, usually one-sided, sometimes bilateral. It is characterized by moderate to severe pain, which worsens with physical activity and may be associated with nausea and vomiting, may be accompanied by photophobia and phonophobia. The disorder can occur at any [...] Read more.

Migraine is a hereditary disease, usually one-sided, sometimes bilateral. It is characterized by moderate to severe pain, which worsens with physical activity and may be associated with nausea and vomiting, may be accompanied by photophobia and phonophobia. The disorder can occur at any time of the day and can last from 4 to 72 h, with and without aura. The pathogenic mechanism is unclear, but extensive preclinical and clinical studies are ongoing. According to electrophysiology and imaging studies, many brain areas are involved, such as cerebral cortex, thalamus, hypothalamus, and brainstem. The activation of the trigeminovascular system has a key role in the headache phase. There also appears to be a genetic basis behind the development of migraine. Numerous alterations have been identified, and in addition to the genetic cause, there is also a close association with the surrounding environment, as if on the one hand, the genetic alterations may be responsible for the onset of migraine, on the other, the environmental factors seem to be more strongly associated with exacerbations. This review is an analysis of neurophysiological mechanisms, neuropeptide activity, and genetic alterations that play a fundamental role in choosing the best therapeutic strategy. To date, the goal is to create a therapy that is as personalized as possible, and for this reason, steps forward have been made in the pharmacological field in order to identify new therapeutic strategies for both acute treatment and prophylaxis. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

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14 pages, 1048 KiB

Open AccessReview

Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine

by Gaku Yamanaka, Shinji Suzuki, Natsumi Morishita, Mika Takeshita, Kanako Kanou, Tomoko Takamatsu, Shunsuke Suzuki, Shinichiro Morichi, Yusuke Watanabe, Yu Ishida, Soken Go, Shingo Oana, Yasuyo Kashiwagi and Hisashi Kawashima

Int. J. Mol. Sci. 2021, 22(16), 8929; https://doi.org/10.3390/ijms22168929 - 19 Aug 2021

Cited by 30 | Viewed by 4676

Abstract

Currently, migraine is treated mainly by targeting calcitonin gene-related peptides, although the efficacy of this method is limited and new treatment strategies are desired. Neuroinflammation has been implicated in the pathogenesis of migraine. In patients with migraine, peripheral levels of pro-inflammatory cytokines, such [...] Read more.

Currently, migraine is treated mainly by targeting calcitonin gene-related peptides, although the efficacy of this method is limited and new treatment strategies are desired. Neuroinflammation has been implicated in the pathogenesis of migraine. In patients with migraine, peripheral levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α, are known to be increased. Additionally, animal models of headache have demonstrated that immunological responses associated with cytokines are involved in the pathogenesis of migraine. Furthermore, these inflammatory mediators might alter the function of tight junctions in brain vascular endothelial cells in animal models, but not in human patients. Based on clinical findings showing elevated IL-1β, and experimental findings involving IL-1β and both the peripheral trigeminal ganglion and central trigeminal vascular pathways, regulation of the Il-1β/IL-1 receptor type 1 axis might lead to new treatments for migraine. However, the integrity of the blood-brain barrier is not expected to be affected during attacks in patients with migraine. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

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Other

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10 pages, 1243 KiB

Open AccessBrief Report

A Single Episode of Cortical Spreading Depolarization Increases mRNA Levels of Proinflammatory Cytokines, Calcitonin Gene-Related Peptide and Pannexin-1 Channels in the Cerebral Cortex

by Maria N. Volobueva, Elena M. Suleymanova, Maria P. Smirnova, Alexey P. Bolshakov and Lyudmila V. Vinogradova

Int. J. Mol. Sci. 2023, 24(1), 85; https://doi.org/10.3390/ijms24010085 - 21 Dec 2022

Cited by 8 | Viewed by 1355

Abstract

Cortical spreading depolarization (CSD) is the neuronal correlate of migraine aura and the reliable consequence of acute brain injury. The role of CSD in triggering headaches that follow migraine aura and brain injury remains to be uncertain. We examined whether a single CSD [...] Read more.

Cortical spreading depolarization (CSD) is the neuronal correlate of migraine aura and the reliable consequence of acute brain injury. The role of CSD in triggering headaches that follow migraine aura and brain injury remains to be uncertain. We examined whether a single CSD occurring in awake animals modified the expression of proinflammatory cytokines (Il1b, TNF, and Il6) and endogenous mediators of nociception/neuroinflammation-pannexin 1 (Panx1) channel and calcitonin gene-related peptide (CGRP), transforming growth factor beta (TGFb) in the cortex. Unilateral microinjury of the somatosensory cortex triggering a single CSD was produced in awake Wistar rats. Three hours later, tissue samples from the lesioned cortex, intact ipsilesional cortex invaded by CSD, and homologous areas of the contralateral sham-treated cortex were harvested and analyzed using qPCR. Three hours post-injury, intact CSD-exposed cortexes increased TNF, Il1b, Panx1, and CGRP mRNA levels. The strongest upregulation of proinflammatory cytokines was observed at the injury site, while CGRP and Panx1 were upregulated more strongly in the intact cortexes invaded by CSD. A single CSD is sufficient to produce low-grade parenchymal neuroinflammation with simultaneous overexpression of Panx1 and CGRP. The CSD-induced molecular changes may contribute to pathogenic mechanisms of migraine pain and post-injury headache. Full article

(This article belongs to the Special Issue Molecular Research of Migraine: From Pathogenesis to Treatment)

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