Pathogenesis Of Migraine Research Articles

Specificity of Migraine Treatment in Women

The prevalence of migraine is higher in women than in men, with female to male ratio 3:1 in reproductive age. It is believed that sex hormones play significant role in migraine pathogenesis. Therefore, treatment of migraine in women has some specificities due to hormonal differences between sexes and due to hormonal fluctuations during menstrual cycle, pregnancy, lactation and perimenopause. Treatment of migraine during pregnancy depends on safety profile of the therapy. NSAID-s like naproxen and ibuprofen are being considered safe during the second trimester, but during the first and third trimester they may have adverse effects on pregnancy and foetus. CGRP antagonists should be avoided during pregnancy. Acetaminophen, ibuprofen, and diclofenac are considered to be safe acute therapy during breastfeeding and for preventive treatment propranolol should be used as first line therapy. Women with severe menstrual and menstrual related migraine without aura may be treated with hormonal therapy, whereas it should be avoided among patients with aura due to increased risk of stroke.

Neuronal NLRP3 inflammasome mediates spreading depolarization-evoked trigeminovascular activation.

Spreading depolarization (SD), the underlying mechanism of migraine aura, may trigger the opening of the pannexin 1 (PANX1) pore to sustain the cortical neuroinflammatory cascades involved in the genesis of headache. Yet, the mechanism underlying SD-evoked neuroinflammation and trigeminovascular activation remains incompletely understood. We characterized the identity of inflammasome activated following SD-evoked PANX1 opening. Pharmacological inhibitors targeting PANX1 or NLRP3 as well as genetic ablation of Nlrp3 and Il1b were applied to investigate the molecular mechanism of the downstream neuroinflammatory cascades. In addition, we examined whether SD-triggered microglial activation facilitates neuronal NLRP3-mediated inflammatory cascades. Pharmacological inhibition of toll-like receptors TLR2/4, the potential receptors of the damage-associated molecular pattern HMGB1, was further employed to interrogate the neuron-microglia interplay in SD-induced neuroinflammation. We found that NLRP3 but not NLRP1 or NLRP2 inflammasome was activated following PANX1 opening after single or multiple SDs evoked by either KCl topical application or non-invasively with optogenetics. The SD-evoked NLRP3 inflammasome activation was observed exclusively in neurons but not microglia or astrocytes. Proximity ligation assay demonstrated that the assembly of the NLRP3 inflammasome occurred as early as 15 min after SD. Genetic ablation of Nlrp3 or Il1b or pharmacological inhibition of PANX1 or NLRP3 ameliorated SD-induced neuronal inflammation, middle meningeal artery dilatation, calcitonin gene-related peptide expression in trigeminal ganglion and c-Fos expression in trigeminal nucleus caudalis. Moreover, multiple SDs induced microglial activation subsequent to neuronal NLRP3 inflammasome activation, which in turn orchestrated with neurons to mediate cortical neuroinflammation, as demonstrated by decreased neuronal inflammation after pharmacological inhibition of microglia activation or blockade of the TLR2/4 receptors. To conclude, single or multiple SDs evoked activation of neuronal NLRP3 inflammasomes and its downstream inflammatory cascades to mediate cortical neuroinflammation and trigeminovascular activation. In the context of multiple SDs, the cortical inflammatory processes could be facilitated by SD-evoked microglia activation. These findings may implicate the potential role of innate immunity in migraine pathogenesis.

Glibenclamide Posttreatment Does Not Inhibit Levcromakalim Induced Headache in Healthy Participants: A Randomized Clinical Trial

Intravenous infusion of ATP-sensitive potassium channel (KATP) opener levcromakalim causes headache in humans and implicates KATP channels in headache pathophysiology. Whether KATP channel blocker glibenclamide inhibits levcromakalim-induced headache has not yet been elucidated. We aimed to investigate the effect of posttreatment with glibenclamide on levcromakalim-induced headache in healthy participants. In a double blind, randomized, three-arm, placebo-controlled, crossover study, 20 healthy participants were randomized to receive 20 mL of levcromakalim (0.05 mg/min (50 mg/mL)) or 20 mL placebo (isotonic saline) intravenously over 20 min followed by oral administration of 10 mg glibenclamide or placebo. Fifteen participants completed all three study days. The primary endpoint was the difference in incidence of headache (0–12 h) between glibenclamide and placebo. More participants developed headache on levcromakalim-placebo day (15/15, 100%) (P = 0.013) and levcromakalim-glibenclamide day (13/15, 86%) compared to placebo-placebo day (7/15, 46%) (P = 0.041). We found no difference in headache incidence between levcromakalim-placebo day and levcromakalim-glibenclamide day (P = 0.479). The AUC0–12 h for headache intensity was significantly larger in levcromakalim-placebo day and levcromakalim-glibenclamide day compared to placebo-placebo day (106.3 ± 215.8) (P < 0.01). There was no difference in the AUC0–12 h for headache intensity between the levcromakalim-placebo day (494 ± 336.6) and the levcromakalim-glibenclamide day (417 ± 371.6) (P = 0.836). We conclude that non-specific KATP channel inhibitor glibenclamide did not attenuate levcromakalim-induced headache in healthy volunteers. Future studies should clarify the involvement of the distinct isoforms of sulfonylurea receptor subunits of KATP channels in the pathogenesis of headache and migraine.

Botulin therapy for chronic migraine

This article presents a review of current modern research on the use of botulinum toxin therapy for the prevention and treatment of patients with chronic migraine, as well as briefly outlines current views on the pathogenesis of migraine, its impact on quality of life and patients' ability to work. Botulinum toxin A is currently the drug of first choice for the treatment of chronic migraine. Numerous studies confirm the effectiveness and safety of its use in clinical practice.

Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development.

Human organoids are small, self-organized, three-dimensional (3D) tissue cultures that have started to revolutionize medical science in terms of understanding disease, testing pharmacologically active compounds, and offering novel ways to treat disease. Organoids of the liver, kidney, intestine, lung, and brain have been developed in recent years. Human brain organoids are used for understanding pathogenesis and investigating therapeutic options for neurodevelopmental, neuropsychiatric, neurodegenerative, and neurological disorders. Theoretically, several brain disorders can be modeled with the aid of human brain organoids, and hence the potential exists for understanding migraine pathogenesis and its treatment with the aid of brain organoids. Migraine is considered a brain disorder with neurological and non-neurological abnormalities and symptoms. Both genetic and environmental factors play essential roles in migraine pathogenesis and its clinical manifestations. Several types of migraines are classified, for example, migraines with and without aura, and human brain organoids can be developed from patients with these types of migraines to study genetic factors (e.g., channelopathy in calcium channels) and environmental stressors (e.g., chemical and mechanical). In these models, drug candidates for therapeutic purposes can also be tested. Here, the potential and limitations of human brain organoids for studying migraine pathogenesis and its treatment are communicated to generate motivation and stimulate curiosity for further research. This must, however, be considered alongside the complexity of the concept of brain organoids and the neuroethical aspects of the topic. Interested researchers are invited to join the network for protocol development and testing the hypothesis presented here.

ONE-CARBON METABOLISM GENE POLYMORPHISM CORRELATE WITH LEVELS OF DNA METHYLTRANSFERASES IN PATIENTS WITH MIGRAINE

Migraine is a common, disabling disorder characterized by attacks of 4 to 72 h of severe headache and associated autonomic and neurological symptoms.&nbsp;In the present study we analyzed the expression of DNMT1, DNMT3a, and DNMT3b in patients with migraine compared with healthy controls as well as the association between the levels of DNMTs and the LINE-1 methylation status in migraine patients with MTHFR C677T variant. Materials and Method: A total 48 individuals were enrolled in this study (24 patients with migraine and 24 age-matched healthy controls). The study protocol was approved by the Ethics Committee of Tbilisi State Medical University. Results: We observed that methylation of LINE-1 were correlated with the levels of&nbsp;DNMT3a in migraine. In addition, levels of DNMT1, DNMT3a and DNMT3b in patients with TT genotypes of MTHFR gene rs1801133 polymorphism were significantly lower compared with individuals with CC genotypes. Conclusions: Differential levels DNMTs may play an important role in the pathogenesis of migraine. Further investigation of enzymes involved in DNA methylation with larger number of samples may provide important insight into the development of novel treatments for episodic and/or chronic migraine.

Temporal alterations of pituitary adenylate cyclase activating polypeptide and its receptors in a rat model induced by recurrent chemical stimulations: Relevant to chronic migraine.

Background: Migraine is a common type of primary headache with disabling brain dysfunction. It has been found that pituitary adenylate cyclase activating polypeptide (PACAP) is involved in the pathogenesis of migraine, however, the role of PACAP and its receptors in chronic migraine remains unclear. Therefore, the present study aimed to explore the changes of PACAP and its receptors in different duration after recurrent dural inflammation soup stimulations and to investigate the co-expression between PACAP and calcitonin gene-related peptide (CGRP). Methods: Adult male rats were implanted with cannula surrounding superior sagittal sinus, which was followed by dural infusion of inflammatory soup (IS) or normal saline (NS). The rats were randomly divided into 4 groups (n = 8 for each group): IS stimulation for seven days (IS-7 group), IS stimulation for 14days (IS-14 group), IS stimulation for 21days (IS-21 group), and NS control for 21days (CON group). The facial mechanical withdrawal threshold was daily measured during the whole experiment. The behavioral changes (ipsilateral and bilateral face grooming behavior) in a plastic cage of rats were observed and recorded. The expression of PACAP, its receptors (PAC1, VPAC1, VPAC2), and CGRP in the trigeminal ganglia (TG) and the trigeminal nucleus caudalis (TNC) was examined by immunohistochemistry. Immunofluorescence was used to explore the co-expression of PACAP, PAC1 receptor, and CGRP after repeated IS administration in the TG. Results: The ipsilateral facial grooming time of IS-21 group displayed an apparent increase than CON group after repeated stimulation on day 2, while significant differences were observed on day 14. No differences were found between the IS-21 and CON group in bilateral facial grooming. Dural IS stimulation induced a significantly decrease in facial mechanical withdrawal thresholds. PACAP positive cells in the regions of TNC were gradually decreased with the IS days increasing. PACAP and PAC1 receptor expression in the TG had a trend of increasing first and then decreasing. There was no significant difference in expression of VPAC1 and VPAC2 in the TG and the TNC. Immunofluorescence showed that PACAP was mainly expressed in TG neurons. PACAP and PAC1 receptor co-expression decreased gradually after repetitive IS stimulation. While the co-expression between PACAP and CGRP reached the peak in IS-7 group after repetitive IS stimulation, and then decreased. Conclusions: This study demonstrated that repetitive chemical stimulations induced a gradual decrease of PACAP in the TNC, while the PACAP and PAC1 receptor expression in TG showed dynamical changes of increasing first and then decreasing after repeated IS administration. These results suggested exhaustion of PACAP could be involved in the duration of chronic migraine and implied PACAP may contribute to the pathology of migraine through the PAC1 receptor, which was associated with CGRP.

Astrocyte-Microglia Crosstalk: A Novel Target for the Treatment of Migraine.

Migraine is a pervasive neurologic disease closely related to neurogenic inflammation. The astrocytes and microglia in the central nervous system are vital in inducing neurogenic inflammation in migraine. Recently, it has been found that there may be a crosstalk phenomenon between microglia and astrocytes, which plays a crucial part in the pathology and treatment of Alzheimer's disease and other central nervous system diseases closely related to inflammation, thus becoming a novel hotspot in neuroimmune research. However, the role of the crosstalk between microglia and astrocytes in the pathogenesis and treatment of migraine is yet to be discussed. Based on the preliminary literature reports, we have reviewed relevant evidence of the crosstalk between microglia and astrocytes in the pathogenesis of migraine and summarized the crosstalk pathways, thereby hoping to provide novel ideas for future research and treatment.

Dietary zinc intake and migraine in adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999-2004.

The study examined the relationship between dietary zinc intake and migraine. Neuroinflammatory and oxidative stress are involved in the pathogenesis of migraine. Little is known about the effects of zinc, an anti-inflammatory and antioxidant trace element, on migraine. The US National Health and Nutrition Examination Survey data from 1999 to 2004 were analyzed for this cross-sectional study. Participants who had severe headache or migraine were classified as having migraine. Dietary zinc intake was evaluated using the 24 h dietary recall system. A total of 11,088 participants were included, of whom, 20.2% (2236/11,088) reported having migraine disease. Compared to the lowest dietary zinc intake quintile (Q1, ≤5.9mg/day), the adjusted odds ratios for migraine in Q2 (6.0-8.4mg/day), Q3 (8.5-11.2mg/day), Q4 (11.3-15.7mg/day), and Q5 (≥15.8mg/day) were 0.73 (95% confidence interval [CI]: 0.61-0.88, p=0.004), 0.71 (95% CI: 0.56-0.91, p=0.013), 0.71 (95% CI: 0.57-0.90, p=0.008), and 0.70 (95% CI: 0.52-0.94, p=0.029), respectively. Sensitivity analysis of zinc supplementation survey participants also showed an association between dietary zinc intake and migraine. Compared to the lowest total zinc intake quintile (Q1: 0.5-9.6mg/day), the adjusted odds ratios for migraine in Q3 (19.3-24.3mg/day) and Q4 (24.4-32.5mg/day) were 0.62 (95% CI: 0.46-0.83, p=0.019) and 0.67 (95% CI: 0.49-0.91, p=0.045), respectively. Our findings indicate an inverse association between dietary zinc intake and migraine in adult Americans.

Different Aspects of Aging in Migraine.

Migraine is a common neurological disease displaying an unusual dependence on age. For most patients, the peak intensity of migraine headaches occurs in 20s and lasts until 40s, but then headache attacks become less intense, occur less frequently and the disease is more responsive to therapy. This relationship is valid in both females and males, although the prevalence of migraine in the former is 2-4 times greater than the latter. Recent concepts present migraine not only as a pathological event, but rather as a part of evolutionary adaptive response to protect organism against consequences of stress-induced brain energy deficit. However, these concepts do not fully explain that unusual dependence of migraine prevalence on age. Many aspects of aging, both molecular/cellular and social/cognitive, are interwound in migraine pathogenesis, but they neither explain why only some persons are affected by migraine, nor suggest any causal relationship. In this narrative/hypothesis review we present information on associations of migraine with chronological aging, brain aging, cellular senescence, stem cell exhaustion as well as social, cognitive, epigenetic, and metabolic aging. We also underline the role of oxidative stress in these associations. We hypothesize that migraine affects only individuals who have inborn, genetic/epigenetic, or acquired (traumas, shocks or complexes) migraine predispositions. These predispositions weakly depend on age and affected individuals are more prone to migraine triggers than others. Although the triggers can be related to many aspects of aging, social aging may play a particularly important role as the prevalence of its associated stress has a similar age-dependence as the prevalence of migraine. Moreover, social aging was shown to be associated with oxidative stress, important in many aspects of aging. In perspective, molecular mechanisms underlying social aging should be further explored and related to migraine with a closer association with migraine predisposition and difference in prevalence by sex.

The Effects of Vitamin B-Complex Supplementation on Serum Homocysteine Levels and Migraine Severity in Children A Randomized Controlled Trial.

Given that deficiency in B vitamins can lead to the accumulation of homocysteine (Hcy), and hyperhomocysteinemia may have a role in migraine pathogenesis, the present prospective randomized double-blinded placebo-controlled trial aimed to evaluate the effect of vitamin B-complex supplementation on the alleviation of migraine in children through a possible reduction in Hcy levels. Ninety children under 15 years of age suffering from typical migraine were included in the present trial. They were randomly assigned into two groups (forty-five patients in each group) to receive either vitamin B-complex or a matching placebo for six months. Serum Hcy levels and headache characteristics were evaluated and compared before and after administering vitamin B-complex or placebo. Unlike the placebo group, the monthly headache frequency, severity of headache, headache disability, and serum Hcy levels were significantly decreased after the vitamin administration. The headache duration was not significantly different before and after the treatment. In the vitamin group, there were significant positive correlations between the frequency and severity, frequency and disability, and severity and disability of headaches. Hcy also had significant positive correlations with the frequency and disability of headaches. In the placebo group, the only found significant correlation was between headache frequency and disability. The administration of vitamin B-complex might effectively relieve migraine severity in children by reducing serum Hcy. However, further studies are needed to confirm the results.

Triggers, Diagnosis and Treatment of Migraine in Primary Care

Migraine remains the second leading cause of disability worldwide. Typically, diagnosis is based on the patient's medical history and clinical examination, and imaging studies are usually unnecessary. Migraine can be classified according to the presence or absence of aura and the frequency of headaches. Migraine can occur episodically or become chronic. Although the exact cause of migraine remains unknown, studies suggest that the trigeminovascular system plays a role in the perception of migraine pain. The most commonly reported migraine triggers include stress, fatigue, fasting, sensory stimuli, hormonal changes, and sleep disturbances. Treatment options include acute, preventive, and non-pharmacological therapies. Recent progress in understanding migraine pathogenesis has led to the development of new mechanism-based medications, expanding the range of available treatments. Tailoring treatment plans to individual patients' clinical characteristics, preferences, and needs is important.

Increased visinin-like protein-1, YKL-40, lipocalin-2, and IL-23 levels in patients with migraine

ABSTRACT Background Migraine is a type of primary headache caused by changes in the trigeminal system and has been reported to be associated with neurovascular inflammation of cerebral and extracerebral vessels. Objective It is known that inflammation is an important process in the pathogenesis of migraine. It has been shown that the molecules of visinin-like protein 1 (Vilip-1), YKL-40, lipocalin-2 and interleukin (IL)-23 play a role in the inflammatory process. Our aim is to investigate the role of this molecule in the metabolic pathway of migraine disease. Methods Fifty migraine patients with and without aura in the interictal period were included in the study. Vilip-1, YKL-40, lipocalin-2, and IL-23 levels were measured by ELISA method. Results Serum vilip-1, YKL-40, lipocalin-2, and IL-23 levels were found to be significantly higher in migraine patients compared to the control group. We found that this molecule increased significantly in migraine subgroups compared to the control group (p < 0.001). A positive significant correlation was found between vilip-1 level and YKL-40 and lipocalin-2 levels in migraine patients. In addition, a positive correlation was observed between visual analogue scale score, number of days with pain and vilip-1 level (p < 0.01). The results of our study showed that activation of inflammatory mediators may play a role in the pathogenesis of migraine disease. In addition, our study is valuable in that inflammatory molecules are high in the interictal period and these biomarkers have never been analyzed in migraine patients. However, we still believe that larger studies are needed to explain the role of vilip-1, YKL-40, lipocalin-2, and IL-23 in the molecular mechanism of migraine disease.

A study on alterations in functional activity in migraineurs during the interictal period

Migraine is a recurrent disease in which the cumulative effect of repeated pain attacks over a long period of time causes changes in brain function. Although there are some studies focusing on the interictal period of migraine, the reproducibility of these results is poor. Therefore, we intend to use a data-driven functional connectivity (FC) approach to probe the alterations in cerebral functional activity during the interictal period, as well as underlying no-task mechanisms of inducing headache attack in migraine patients. In the current research, 24 episodic migraine patients and 23 healthy controls (HCs) were recruited. By analyzing the magnitude of regional homogeneity (ReHo) and low-frequency fractional fluctuation (fALFF), We identified alterations in spontaneous brain activity in migraineurs, including the bilateral middle frontal gyrus, left postcentral, and right lingual gyrus. Thereafter such abnormalities were selected as seeds (ROIs) for FC analysis to further explore the underlying changes between ROIs and the whole brain areas. Compared with HCs, FC between the right middle frontal gyrus with the left precuneus cortex, and bilateral thalamus were enhanced in migraineurs. In addition, increased FC has been showed between the left postcentral gyrus with the bilateral thalamus. Furthermore, negative correlation existed between fALFF values of the left middle frontal gyrus and the pain intensity of migraine attacks (r = −0.4578, p = 0.0245). In summary, abnormal FC between the bilateral thalamus and right middle frontal gyrus, or the left retrocentral gyrus may occur between attacks in migraineurs, which may be the basis for sensory integration and pain regulation dysfunction. Thus, this could become a promising biomarker for the early diagnosis and evaluation of migraine in the interictal period, and provide a novel view for further investigation of the pathogenesis and etiology of recurrent migraine.

GLOBAL DNA METHYLATION LEVELS IN MIGRAINE PATIENTS FROM GEORGIA

Introduction: Migraine is a common, complex neurological disease characterized by the presence of a strong genetic component. Genome-wide association studies (GWAS) have identified gene variants involved in migraine development. In addition, it is known that epigenetic mechanisms, such as DNA methylation, play an important role in inflammation disorders. The aim of our study was to investigate global DNA methylation levels in migraine patients with C677T polymorphism of the MTHFR gene. Materials and methods: MTHFR C677T genotyping analysis (36 patients and 32 controls) was performed using TaqMan technology (Thermo Scientific, USA). Global DNA methylation was determined by the quantitative analysis of 5-methylcytosine (Zymo Research, Germany). Results: In individuals with TT genotypes, the percentage of methylated cytosine (5mC) was significantly lower in the migraine group compared to the control group (P=0.001). Conclusions: Our results suggest that epigenetic approaches can be used to study the migraine pathogenesis. In addition, reduced methylation levels can be ameliorated by the dietary supplementation with vitamins B6, B9, B12, which may be a strategy for migraine prevention and management in patients with MTHFR C677T polymorphism.

Potentially Remediable Shortcomings in the Contemporary Drug Treatment of Migraine

Despite the availability over the past decade of a number of new pharmaceutical agents with different mechanisms of action from those of the drugs used previously, the contemporary drug therapy of migraine attacks falls rather short of what would be desirable, while the pharmacological attempt to prevent further attacks appears to prove unsatisfactory about as often as it is successful. The present paper explores reasons for these shortcomings in both the earlier and the current drug therapy of the disorder. Significant major contributory factors appear to be an incomplete understanding of the underlying pathogenic mechanisms of the various stages of the migraine attack, less than optimal pharmacokinetic characteristics of many of the drugs used, and migraine sufferers failing to employ the available drugs to their best advantage. New drugs developed in the light of a more complete understanding of the molecular basis of migraine pathogenesis, together with awareness of pharmacokinetic desiderata in relation to treating and preventing migraine attacks, may go some way towards remedying the situation, but patient decision making may prove more difficult to modify.

Alteration of gut microbiota in migraine patients with irritable bowel syndrome in a Chinese Han population.

Migraine is frequently reported in patients with irritable bowel syndrome (IBS), and emerging evidence suggests that gut microbiota plays a role in migraine and IBS. However, alterations in the gut microbiome in migraine patients with IBS remain unknown. This study aimed to explore the compositions of gut microbiota in migraine patients with IBS in a Chinese Han population. Sixteen migraine patients with IBS and thirteen age- and gender-matched IBS patients with similar dietary and lifestyle habits were enrolled in this pilot study. Demographic data, clinical data, eating habits, lifestyle habits, comorbidities, and medications were recorded using a unified case registration form. Questionnaires for the Migraine Disability Assessment (MIDAS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) were completed. Fecal samples were collected, and microbial DNA was extracted. Gut microbiota 16S ribosomal RNA (16S rRNA) gene sequencing targeting the V4 region was performed using the Illumina HiSeq 2500 high-throughput sequencing platform. The relationships between gut microbiota and clinical characteristics of migraine were analyzed. The structure of gut microbiota differed between migraine patients with IBS and patients with IBS, while the richness and diversity of gut microbiota in migraine patients with IBS showed no significant difference from that of patients with IBS. We found a higher relative abundance of the genus Parabacteroides and a lower relative abundance of the genera Paraprevotella, Lachnospiraceae_UCG-010, Lactococcus, Collinsella, and Comamonas in migraine patients with IBS than in patients with IBS. According to random forest predictive models, the phylum Bacteroidota shows the most important role in migraine patients with IBS. Furthermore, no statistical correlation was found between significantly different taxa at the genus level and migraine clinical data. This study identified that altered gut microbiota occurred in Chinese Han migraine patients with IBS, but no correlation was found between gut microbiota and the clinical characteristics of migraine. Further study is needed to better understand the role of gut microbiota in the pathogenesis of migraine in IBS.

Sustained Effects of CGRP Blockade on Cortical Spreading Depolarization-Induced Alterations in Facial Heat Pain Threshold, Light Aversiveness, and Locomotive Activity in the Light Environment.

A migraine is clinically characterized by repeated headache attacks that entail considerable disability. Many patients with migraines experience postdrome, the symptoms of which include tiredness and photophobia. Calcitonin gene-related peptide (GGRP) is critically implicated in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, sensitizes the trigeminovascular system. In our previous study, CSD caused hypomotility in the light zone and tendency for photophobia at 72 h, at which time trigeminal sensitization had disappeared. We proposed that this CSD-induced disease state would be useful for exploring therapeutic strategies for migraine postdrome. In the present study, we observed that the CGRP receptor antagonist, olcegepant, prevented the hypomotility in the light zone and ameliorated light tolerability at 72 h after CSD induction. Moreover, olcegepant treatment significantly elevated the threshold for facial heat pain at 72 h after CSD. Our results raise the possibility that CGRP blockade may be efficacious in improving hypoactivity in the light environment by enhancing light tolerability during migraine postdrome. Moreover, our data suggest that the CGRP pathway may lower the facial heat pain threshold even in the absence of overt trigeminal sensitization, which provides an important clue to the potential mechanism whereby CGRP blockade confers migraine prophylaxis.

Role of Peripheral Inflammatory Markers in Patients with Acute Headache Attack to Differentiate between Migraine and Non-Migraine Headache.

Although the potential relationship between headaches, particularly migraine, and peripheral inflammatory markers (PIMs) has been investigated, it is unclear whether PIMs are involved in the pathogenesis of migraine or can differentiate it from non-migraine headaches (nMHs). Using 10 years of data from the Smart Clinical Data Warehouse, patients who visited the neurology outpatient department (OPD) within 30 days after visiting the emergency room (ER) for headaches were divided into migraine and nMH groups, the PIMs were compared including the neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR) ratios, and neutrophil-to-monocyte ratio (NMR). Of the 32,761 patients who visited the ER for headaches, 4005 patients visited the neurology OPD within 30 days. There were significant increases in the NLR, MLR, and NMR, but a lower PLR in the migraine and nMH groups than the controls. The NMR was significantly higher in the migraine than the nMH group. A receiver operating characteristic curve analysis showed that the ability of the NLR and NMR to differentiate between migraine and nMHs was poor, whereas it was fair between the migraine groups and controls. The elevated PIMs, particularly the NLR and NMR, during headache attacks in migraineurs suggest that inflammation plays a role in migraine and PIMs may be useful for supporting a migraine diagnosis.

BAY-117082-driven NLRP3 inflammasome inhibition resolves nitro-glycerine (NTG) neuronal damage in in vivo model of migraine

Migraine is a common neuronal disorder characterized by recurrent episodes of headache associated with a higher prevalence in women than men. Several risk factors have been associated with migraine disease as genetic factors, gender, and age. Although understanding migraine pathophysiology is improved, it has been reported that NOD-like receptor protein 3 (NLRP3) inflammasome pathway overactivation can contribute to migraine progression. Therefore, the aim of this study was to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in a mouse model of nitroglycerin (NTG)-induced migraine. The in vivo model of migraine was induced by intraperitoneal (i.p) injection of NTG (dose of 10 mg/kg). Mice were treated intraperitoneally with BAY-117082 at doses of 1 mg/kg, 5 mg/kg, and 10 mg/kg, 5 min following NTG injection. After 4 h of NTG injection, the whole brain tissue with the rostral spinal cord were collected and used to perform further analysis. Our results demonstrated that BAY-117082 treatments (5 mg/kg and 10 mg/kg) reduced pain attacks, hyperalgesia and photophobia more in female mice NTG-induced. Moreover, the treatment with BAY-117082 significantly reduced histological damage in the trigeminal nerve nucleus in female mice accordingly to significantly decreased in NLRP3 complex components expression levels such as ASC, IL-1β, IL-18, caspase-1 and TNF-α levels. Additionally, the treatment with BAY-117082 at both higher doses significantly modulated CREB/Erk/Akt pathways strictly correlated to the expression of neurotrophic factors. Taken together, obtained results confer new insight into the role of the NLRP3 inflammasome pathway in migraine pathogenesis, suggesting that BAY-117082 could be considered a novel strategy therapeutics for migraine treatment despite unconventional drug use.