Migraine Pathophysiology Research Articles

MIGRAINE

Background Migraine is a prevalent neurological disorder characterized by chronic headaches, significantly impacting the global population. This comprehensive review aims to advance the understanding of migraine pathogenesis and treatment, focusing on molecular markers and novel therapeutic strategies. Material Molecular markers such as calcitonin gene-related peptide (CGRP) and their role in migraine development. Traditional medical treatments and emerging therapeutic strategies, including neuromodulation, are analyzed for their effectiveness and limitations. Clinical studies and imaging techniques are leveraged to identify key mechanisms and triggers in migraine pathology. Approximately 95% of people experience a headache at some point, with migraines being a significant contributor. Migraine is recognized by the World Health Organization as one of the top ten causes of disability globally, particularly affecting women. CGRP is identified as a crucial factor in migraine development. Inhibitors targeting CGRP have shown significant effectiveness in managing migraines. Other molecular markers, including proinflammatory cytokines and neurotransmitters, are discussed for their roles in pain transmission and migraine pathophysiology. Traditional treatments, such as triptans and NSAIDs, are evaluated alongside new therapies, including CGRP inhibitors and neuromodulation techniques. Neuromodulation, involving devices like external trigeminal nerve stimulators, shows promise in migraine management. Genetic markers associated with familial hemiplegic migraine (FHM) and common migraine forms are reviewed. Recent genome-wide association studies (GWAS) have identified several genetic variants linked to migraine susceptibility. Conclusion This presentation enhances the understanding of migraine pathogenesis and introduces novel therapeutic possibilities. By focusing on molecular markers like CGRP and exploring advanced treatment options, the study aims to improve migraine management and patient care. The findings underscore the need for continued research and innovation in migraine treatments to reduce the global burden of this debilitating condition.

Magnetoencephalography studies in migraine and headache disorders: A systematic review.

Understanding the neural mechanisms underlying migraine and other primary headache disorders is critical for the development of long-term cures. Magnetoencephalography (MEG), an imaging modality that measures neuronal currents and cortical excitability with high temporal and superior spatial resolution, has been increasingly used in neurological research. Initial MEG studies showed promise in directly recording cortical spreading depression-a cortical correlate of migraine with aura. However, lately MEG technology has highly evolved with greater potential to reveal underlying pathophysiology of migraine and primary headache disorders, and aid in the identification of biomarkers. To systematically review the use of MEG in migraine and other primary headache disorders and summarize findings. We conducted a systematic search and selection of MEG studies in migraine and primary headache disorders from inception until June 8, 2023, in Medline, Embase, Cochrane, and Scopus databases. Peer-reviewed English articles reporting the use of MEG for clinical or research purposes in migraine and primary headache disorders were selected. We found 560 articles and included 38 in this review after screening. Twelve studies investigated resting-state, while others investigated a sensory modality using an evoked or event-related paradigm with a total of 35 cohort and 3 case studies. Thirty-two studies focused exclusively on migraine, while the rest reported other primary headache disorders. The findings show an evolution of MEG from a 7- to a 306-channel system and analysis evolving from sensor-level evoked responses to more advanced source-level connectivity measures. A relatively few MEG studies portrayed migraine and primary headache disorders as a sensory abnormality, especially of the visual system. We found heterogeneity in the datasets, data reporting standards (due to constantly evolving MEG technology and analysis methods), and patient characteristics. Studies were inadequately powered and there was no evidence of blinding procedures to avoid selection bias in case-control studies, which could have led to false-positive findings. More studies are needed to investigate the affective-cognitive aspects that exacerbate pain and disability in migraine and primary headache disorders.

Sex differences in expression of CGRP family of receptors and ligands in the rat trigeminal system

BackgroundCalcitonin gene-related peptide (CGRP) is part of the calcitonin peptide family, which includes calcitonin (CT), amylin (AMY), and adrenomedullin (ADM). CGRP and its receptor are highly present in the trigeminovascular system (TVS). Recent research suggests that other members of the calcitonin family could be feasible therapeutic targets in the treatment of migraine. The present study aims to elucidate the distribution of ADM, AMY, CT, and their receptors in the rat TVS, and to explore potential sex differences in their expression.MethodsTrigeminal ganglia (TG) were dissected from male and female adult rats. Protein and gene expression were assessed through immunohistochemistry and RT-qPCR. Additionally, the dura mater was isolated for further investigation of protein expression and fiber localization using immunohistochemistry.ResultsQuantitative gene expression analysis revealed the presence of all genes in male and female TGs, except for calcitonin receptor (CTR). Notably, CGRP mRNA levels in TG were several folds higher than those of other genes. The receptor activity-modifying protein-1 (RAMP1) mRNA levels were significantly higher in female compared to male.No AMY or CT immunoreactivity was observed in the TVS. In contrast, immunoreactivity for ADM, CGRP, RAMP1, CTR, and calcitonin-like receptor (CLR) were observed in the cytoplasm of TG neurons. Immunoreactive Aδ-fibers storing RAMP1, ADM and CLR were also identified. RAMP2 and RAMP3 were expressed in nucleus of TG neurons and in satellite glial cells. Furthermore, RAMP1 and CLR were co-localized with CASPR in the nodes of Ranvier located in Aδ-fibers.ConclusionsThis study provides valuable insights into the distribution of the CGRP family of peptides and their receptors in the TVS. CGRP mRNA levels in the TG were markedly higher than those of other genes, demonstrating the key role of CGRP. The co-localization of CLR and RAMP1 on Aδ-fibers with CASPR suggests a potential role for this receptor in modulating trigeminal nerve function and neuronal excitability, with implications for migraine pathophysiology. Additionally, RAMP1 mRNA levels were significantly higher in female TG compared to males, indicating sex-specific differences in gene expression. These findings underscore the need for further research into the functional significance of gender-related variations.

The socio-economic burden of migraine: yesterday and today

Migraine is the most frequent and costly type of headache. The analysis of the «cost of the disease» implies an assessment of direct and indirect costs expressed in monetary units. Drastic changes have recently occurred in approaches to the treatment of the disease, in connection with which there are large differences in the structure of the economic burden «yesterday and today». «Yesterday» knowledge about the pathophysiology of migraine was insufficient and various nonspecific agents were used to treat the disease, the antimigrenous effect of which was manifested as an additional one. The relatively low prices of these ineffective drugs for relieving attacks and preventing migraines were accompanied by high indirect costs due to temporary disability of patients, frequent time off from work, decreased labor productivity, family troubles, etc. Therefore, «yesterday»: the indirect costs associated with migraine therapy outweighed the direct costs. «Today» the cost of drugs for the prevention and pathogenetic agents for the relief of migraine attacks has become significantly higher and their costs are the main part of the costs of migraine therapy, However, the effectiveness of new pathogenetic agents for the treatment of migraines helps to reduce indirect costs and improve the quality of life. Awareness of the change in the ratio of direct and indirect costs, as well as the causes of this phenomenon, will increase patient compliance, correctly allocate costs and ultimately save personal and public financial resources.

Topiramate Inhibits Capsaicin-Induced Mast Cell Degranulation and CGRP Release in Rat Dura Mater

Background/Objectives: Migraine is a disease that stands out for its high prevalence and socioeconomic costs. It involves the entire trigeminovascular system, the signaling substances, and their targets. However, the role of meningeal mast cells in migraine is still unclear. To better understand one of the components of neurogenic inflammation underlying migraine pathophysiology, we developed an in vivo rat model in which the dura mater was exposed bilaterally to investigate the influence of topiramate on capsaicin-induced mast cell degranulation and CGRP release from dura mater. Methods: On the day of the experiment, rats were anesthetized, and a craniectomy was performed on each parietal bone. Test substances were applied in situ over the dura mater using the right and left sides of the dura mater for the test and control, respectively. After exposure, the dura mater was processed for mast cell staining and counting. Using this setup, the effect of capsaicin (10−3 M) was evaluated in rats of both sexes, and subsequently the effect of in situ (10−3 M, 20 µL) and (20 mg/kg/day for 10 days) topiramate treatment on mast cell degranulation and CGRP release were evaluated. Results: In both female and male rats, there was a greater amount of degranulated mast cells in the side stimulated by capsaicin compared to the control side in both females (18 ± 3% vs. 74 ± 3%; p = 0.016) and males (28 ± 2% vs. 74 ± 3%, p = 0.016). In the group treated with topiramate for 10 days prior to the experiments, capsaicin did not induce mast cell degranulation (control 20 ± 1% vs. capsaicin 22 ± 1%, p = 0.375) in contrast to animals treated for 10 days with gavage control (control 25 ± 1% vs. capsaicin 76 ± 1%, p = 0.016). Topiramate applied in situ concomitant with capsaicin did not protect the mast cells from degranulation in response to capsaicin (38 ± 2% vs. 44 ± 1%, p = 0.016). There was a significant reduction in CGRP release from the dura mater in the group treated with topiramate for 10 days compared to the control. Conclusions: This study demonstrates a novel experimental model wherein systemic administration of topiramate is observed to modulate the impact of capsaicin on meningeal mast cell degranulation.

MetaCGRP is a high-precision meta-model for large-scale identification of CGRP inhibitors using multi-view information

Migraine is considered one of the debilitating primary headache conditions with an estimated worldwide occurrence of approximately 14–15%, contributing highly to factors responsible for global disability. Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a crucial role in the pathophysiology of migraines and thus, its inhibition can help relieve migraine symptoms. However, conventional process of CGRP drug development has been laborious and time-consuming with incurred costs exceeding one billion dollars. On the other hand, machine learning (ML)-based approaches that are capable of accurately identifying CGRP inhibitors could greatly facilitate in expediting the discovery of novel CGRP drugs. Therefore, this study proposes a novel and high-accuracy meta-model, namely MetaCGRP, that can precisely identify CGRP inhibitors. To the best of our knowledge, MetaCGRP is the first SMILES-based approach that has been developed to identify CGRP inhibitors without the use of 3D structural information. In brief, we initially employed different molecular representation methods coupled with popular ML algorithms to construct a pool of baseline models. Then, all baseline models were optimized and used to generate multi-view features. Finally, we employed the feature selection method to optimize the multi-view features and determine the best feature subset to enable the construction of the meta-model. Both cross-validation and independent tests indicated that MetaCGRP clearly outperforms several conventional ML classifiers, with accuracies of 0.898 and 0.799 on the training and independent test datasets, respectively. In addition, MetaCGRP in conjunction with molecular docking was utilized to identify five potential natural product candidates from Thai herbal pharmacopoeia and analyze their binding affinity and interactions to CGRP. To facilitate community-wide efforts in expediting the discovery of novel CGRP inhibitors, a user-friendly web server for MetaCGRP is freely available at https://pmlabqsar.pythonanywhere.com/MetaCGRP.

Prevalence and features of headache in Parkinson's disease: the role of dopamine.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, but dopamine also plays a role in the pathophysiology of migraine. The aim of this study is to assess lifetime and previous year prevalence rates of headache in PD patients compared with controls. We enrolled 101 patients (57M and 44W) and 101 controls (62M and 39W), comparable for age and gender, who underwent a semi-structured questionnaire to assess the occurrence and the features of headache, and Beck Depression Inventory (BDI). We did not find any significant differences in the overall prevalence of lifetime and last 12-month headache between the two groups, as well as lifetime and last year tension-type headache (TTH) and migraine. Patients, especially those suffering from migraine and treated with dopamine agonists (DA), more frequently showed headache remission after the onset of motor symptoms compared to the age-related remission observed in controls(p = 0.001). Patients affected by headache were less frequently treated with DA in comparison with those without (p = 0.051). Depression of mood was more severe among PD patients with migraine than with TTH (p = 0.021). PD patients with headache exhibiting the akinetic-rigid subtype more frequently reported motor fluctuations than those presenting with tremor-dominant disease (p = 0.040). The prevalence of headache in PD follows that described in the general population, but dopaminergic pathway degeneration, loss of dopamine activation on the trigeminal-vascular system, and DA treatment might favor migraine improvement and remission in PD patients.

Decoding Visual Responses: Insights into Chronic Migraine and Medication Overuse Headache with Electrophysiological Analysis.

Background/Objectives: Habituation and sensitization are opposite phenomena that play a role in the pathophysiology of episodic migraine and its progression to chronic migraine (CM). There have been just a few studies that have investigated these phenomena in patients with medication overuse headache (MOH) in comparison to those with chronic migraine (CM) and healthy controls (HCs), and the findings have been inconsistent. Methods: We measured and examined visual evoked potentials (VEPs) in 81 patients with MOH and 24 patients with CM, as well as 24 HCs. The VEPs were used to assess sensitization by analysing the amplitude of the first block (100 sweeps) and to evaluate habituation by measuring the amplitude response decrement after six blocks. We further examined patients diagnosed with MOH based on their acute medication type and after a 3-week acute medication withdrawal program. Results: There were no significant differences between groups in terms of the first N1-P1 VEP amplitude block and its habituation. It was found that patients with MOH had a greater drop in the amplitude of the VEP P1-N2 complex after repeated stimulation than patients with CM or HC. The VEP parameters showed no significant differences based on the specific overused drug and after a 3-week acute medication withdrawal. Conclusions: We propose that the results obtained in patients with MOH indicate an abnormal activation of inhibitory circuits in the parieto-occipital region in response to repeated modulatory stimuli.

Effects of passive smoking on cortical spreading depolarization in male and female mice

BackgroundPatients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura.FindingsFifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex.ConclusionsFemale mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference.

Exploring the Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Kynurenine Pathway Dysregulation in Migraine Pathophysiology Among Women With Polycystic Ovary Syndrome (PCOS).

A narrative review was undertaken to explore the current understanding of the relationship between polycystic ovary syndrome and migraine headaches, with a focus on the potential roles of pituitary adenylate cyclase-activating polypeptide and the kynurenine pathway in the shared pathophysiology of these conditions. Emerging evidence suggests that pituitary adenylate cyclase-activating polypeptide may be a key player in the development of migraine headaches, with potential implications for the higher incidence of migraine observed in women with polycystic ovary syndrome. Additionally, dysregulation of the kynurenine pathway and altered levels of kynurenine metabolites have been linked to both migraine and polycystic ovary syndrome, indicating a complex interplay between hormonal, metabolic, and neurological factors in the comorbid presentation of these disorders. Further research is needed to elucidate the specific mechanisms underlying these associations and to develop targeted therapeutic approaches for managing migraine in the context of polycystic ovary syndrome.

Insights from triggers and prodromal symptoms on how migraine attacks start: The threshold hypothesis.

The prodrome or premonitory phase is the initial phase of a migraine attack, and it is considered as a symptomatic phase in which prodromal symptoms may occur. There is evidence that attacks start 24-48 hours before the headache phase. Individuals with migraine also report several potential triggers for their attacks, which may be mistaken for premonitory symptoms and hinder migraine research. This review aims to summarize published studies that describe contributions to understanding the fine difference between prodromal/premonitory symptoms and triggers, give insights for research, and propose a way forward to study these phenomena. We finally aim to formulate a theory to unify migraine triggers and prodromal symptoms. For this purpose, a comprehensive narrative review of the published literature on clinical, neurophysiological and imaging evidence on migraine prodromal symptoms and triggers was conducted using the PubMed database. Brain activity and network connectivity changes occur during the prodromal phase. These changes give rise to prodromal/premonitory symptoms in some individuals, which may be falsely interpreted as triggers at the same time as representing the early manifestation of the beginning of the attack. By contrast, certain migraine triggers, such as stress, hormone changes or sleep deprivation, acting as a catalyst in reducing the migraine threshold, might facilitate these changes and increase the chances of a migraine attack. Migraine triggers and prodromal/premonitory symptoms can be confused and have an intertwined relationship with the hypothalamus as the central hub for integrating external and internal body signals. Differentiating migraine triggers and prodromal symptoms is crucial for shedding light on migraine pathophysiology and improve migraine management.

Meningeal KATP channels contribute to behavioral responses in preclinical migraine models

Abstract Human experimental studies have shown that levcromakalim, an ATP-sensitive potassium (KATP) channel opener, induces migraine attacks in people with migraine but not in healthy volunteers. However, the exact site of action for KATP channels in migraine pathophysiology remains unclear. This study investigates the role of these channels in the meninges in eliciting behavioral hypersensitivity responses in mice. The effects of KATP channel signaling were assessed using preclinical migraine models induced by repetitive stress or dural stimulation. Prolactin, CGRP, sodium nitroprusside (SNP), and KATP channel openers or blockers were administered systemically or onto the dura of mice followed by behavioral testing using periorbital von Frey or facial grimace measurements. Repetitive stress sensitized mice to a normally subthreshold systemic dose of levcromakalim. The KATP blocker glibenclamide significantly reduced responses to systemic SNP following repetitive stress. In naive mice, direct dural application of levcromakalim or SNP elicited periorbital hypersensitivity. Responses to dural levcromakalim were inhibited by coinjection with glibenclamide or sumatriptan. By contrast, injection of levcromakalim in the periorbital skin did not induce hypersensitivity. Moreover, repetitive stress sensitized mice to dural injection of normally subthreshold doses of levcromakalim or SNP. Finally, dural coinjection of glibenclamide inhibited periorbital hypersensitivity induced by CGRP or prolactin in female mice. These studies demonstrate that the meninges can be one site of action for the migraine-triggering effects of KATP channel openers. They also show that NO donors, CGRP, and prolactin can produce behavioral hypersensitivity through opening of KATP channels in the meninges.

Abnormal thalamocortical network dynamics in patients with migraine and its relationship with electroacupuncture treatment response.

Acupuncture is an effective and safe alternative treatment to prevent and treat migraine, but its central analgesic mechanism remains poorly understood. It is believed that the dysfunction of the thalamocortical connectivity network is an important contributor to migraine pathophysiology. This study aimed to investigate the abnormal thalamocortical network dynamics in patients with migraine without aura (MWoA) before and after an 8-week electroacupuncture treatment. A total of 143 patients with MWoA and 100 healthy controls (HC) were included, and resting-state functional magnetic resonance imaging (fMRI) data were acquired. Dynamic functional network connectivity (dFNC) was calculated for each subject. The modulation effect of electroacupuncture on clinical outcomes of migraine, dFNC, and their association were investigated. In our results, dFNC matrices were classified into two clusters (brain states). As compared with the HC, patients with MWoA had a higher proportion of brain states with a strong thalamocortical between-network connection, implying an abnormal balance of the network organization across dFNC brain states. Correlation analysis showed that this abnormality was associated with summarized clinical measurements of migraine. A total of 60 patients were willing to receive an 8-week electroacupuncture treatment, and 24 responders had 50% changes in headache frequency. In electroacupuncture responders, electroacupuncture could change the abnormal thalamocortical connectivities towards a pattern more similar to that of HC. Our findings suggested that electroacupuncture could relieve the symptoms of migraine and has the potential capacity to regulate the abnormal function of the thalamocortical circuits.

Traditional Chinese Medicine Use in the Pathophysiological Processes of Migraine

Abstract Migraine is a highly prevalent neurological disorder and has been the second leading cause of disability worldwide for many years. The pathophysiology of migraines is complicated, and most available medications have unpleasant side effects. Therefore, it is essential to understand the mechanism of migraine to develop potential preventive and therapeutic agents. Studies have confirmed that traditional Chinese medicine (TCM) can alleviate migraine by reducing neuroinflammation, oxidative stress, and apoptosis and regulating neurotransmitters and vascular function. Starting from the pathophysiological process of migraine, this review summarizes the mechanisms by which TCM improves neurovascular function after migraine to provide clues and a reference for the clinical application of TCM in the prevention and treatment of migraine and guide further research and development of new drugs.

Involvement of the cerebellum in structural connectivity enhancement in episodic migraine

BackgroundThe pathophysiology of migraine remains poorly understood, yet a growing number of studies have shown structural connectivity disruptions across large-scale brain networks. Although both structural and functional changes have been found in the cerebellum of migraine patients, the cerebellum has barely been assessed in previous structural connectivity studies of migraine. Our objective is to investigate the structural connectivity of the entire brain, including the cerebellum, in individuals diagnosed with episodic migraine without aura during the interictal phase, compared with healthy controls.MethodsTo that end, 14 migraine patients and 15 healthy controls were recruited (all female), and diffusion-weighted and T1-weighted MRI data were acquired. The structural connectome was estimated for each participant based on two different whole-brain parcellations, including cortical and subcortical regions as well as the cerebellum. The structural connectivity patterns, as well as global and local graph theory metrics, were compared between patients and controls, for each of the two parcellations, using network-based statistics and a generalized linear model (GLM), respectively. We also compared the number of connectome streamlines within specific white matter tracts using a GLM.ResultsWe found increased structural connectivity in migraine patients relative to healthy controls with a distinct involvement of cerebellar regions, using both parcellations. Specifically, the node degree of the posterior lobe of the cerebellum was greater in patients than in controls and patients presented a higher number of streamlines within the anterior limb of the internal capsule. Moreover, the connectomes of patients exhibited greater global efficiency and shorter characteristic path length, which correlated with the age onset of migraine.ConclusionsA distinctive pattern of heightened structural connectivity and enhanced global efficiency in migraine patients compared to controls was identified, which distinctively involves the cerebellum. These findings provide evidence for increased integration within structural brain networks in migraine and underscore the significance of the cerebellum in migraine pathophysiology.

Genetic variants associated with response to anti-CGRP monoclonal antibody therapy in a chronic migraine Han Chinese population

BackgroundAnti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine.MethodsWe conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database.ResultsSix single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10− 7): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10− 9). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure.ConclusionThe identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology.Trial registrationNot applicable.

Mechanisms of GTN-induced migraine: Role of NOS isoforms, sGC and peroxynitrite in a migraine relevant mouse model.

Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon. Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312). Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase. Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.

Glial activation in pain and emotional processing regions in the nitroglycerin mouse model of chronic migraine.

Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed.

Study on the comprehensive treatment of migraine with traditional Chinese medicine based on the new pathophysiological mechanism: A review.

Migraine is a ubiquitous neurological disorder that affects approximately 1 billion people worldwide. Migraine is the second leading cause of illness in people of all ages worldwide. Uncertainty in migraine diagnosis leads to unnecessary testing and increases the treatment costs. To date, the pathogenesis of migraine is not fully understood, but it is generally believed that migraine involves the trigeminal nerve and its axonal projections to intracranial blood vessels. Pain signals from the trigeminal neurovascular system are transmitted to the brain, resulting in migraines. As an important component of complementary and alternative medicine, traditional Chinese medicine (TCM) has shown significant efficacy in the treatment of migraine, and has attracted increasing attention worldwide. This review is based on the pathophysiology of migraines in modern medicine. To explore the comprehensive treatment of migraine using TCM, acupuncture, and various other TCM treatments.

The Neuroprotective Role of Indole-3-Propionic Acid in Migraine Pathophysiology.

Background and Objectives: Migraine is a leading cause of disability worldwide, with complex pathophysiological mechanisms involving oxidative and nitrosative stress. Recent research suggests that Indole-3-Propionic Acid (IPA) may have a neuroprotective role in reducing nitrosative stress. This study aims to elucidate the roles of IPA and nitrosative stress biomarkers in migraine patients, focusing on their potential as therapeutic targets. Materials and Methods: This cross-sectional, case-control study included 57 migraine patients and 30 healthy controls. Patients were categorized into episodic migraine (EM) and chronic migraine (CM) groups. Socio-demographic and clinical characteristics were documented through structured interviews. Validated scales such as the Visual Analog Score (VAS), Headache Impact Test 6 (HIT-6), Migraine Disability Assessment Test (MIDAS), Migraine 24 h Quality of Life Scale (24 h QoL), Mini-Mental State Examination (MMSE), and Migraine Attacks-Subjective Cognitive Impairments Scale (Mig-SCog) were administered. Venous blood samples were collected, and serum levels of IPA, Nitric Oxide (NO), Nitric Oxide Synthase (NOS), and Peroxynitrite (ONOO-) were measured using ELISA and spectrophotometric methods. Results: Significant differences in serum IPA and NO levels were observed between migraine patients and controls. Specifically, higher serum IPA levels were found in the EM group, while higher serum NO levels were observed in the CM group. Elevated NO levels correlated with increased migraine attack frequency. Conversely, serum IPA levels showed a negative correlation with attack frequency, suggesting a protective role. Specifically, NO levels were positively correlated with the number of painful days, NSAID usage, VAS scores, HIT-6 scores, and MIDAS scores, while negatively correlated with 24 h QoL scores. Conclusions: The study highlights the significant involvement of IPA and nitrosative stress in migraine pathophysiology. Elevated IPA levels, particularly in EM patients, suggest its potential neuroprotective role. These findings underscore the importance of targeting oxidative and nitrosative stress pathways in developing effective migraine therapies.