calca-protein--human and Migraine-Disorders

A bidirectional causal relationship has been established between temporomandibular disorders (TMDs) and chronic headaches. Recent advances in the neurobiology of chronic pain offer a framework for understanding the comorbidity between these two conditions that might reside in the shared biomolecular mechanisms of peripheral and central sensitization. The initiation of these processes is inflammatory in nature and is most likely mediated by key molecules, including calcitonin gene-related peptide (CGRP). This scoping review proposes that CGRP-mediated neuroinflammation in the trigeminal ganglion may partly explain the biomolecular bidirectional link between TMDs and chronic headaches. Finally, clinical implications of this neuropathologic process are briefly discussed.

Topics: Calcitonin Gene-Related Peptide; Headache Disorders; Humans; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide; Temporomandibular Joint Disorders

Topics: Animals; Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Pituitary Adenylate Cyclase-Activating Polypeptide

There is an unmet need of pharmacological and non-pharmacological treatment options for migraine patients. Exercise can be used in the treatment of several pain conditions, including. However, what exact role exercise plays in migraine prevention is unclear. Here, we review the associations between physical exercise and migraine from an epidemiological, therapeutical and pathophysiological perspective.. The review was based on a primary literature search on the PubMed using the search terms "migraine and exercise".. Low levels of physical exercise and high frequency of migraine has been reported in several large population-based studies. In experimental studies exercise has been reported as a trigger factor for migraine as well as migraine prophylaxis. Possible mechanisms for how exercise may trigger migraine attacks, include acute release of neuropeptides such as calcitonin gene-related peptide or alternation of hypocretin or lactate metabolism. Mechanisms for migraine prevention by exercise may include increased beta-endorphin, endocannabinoid and brain-derived neurotrophic factor levers in plasma after exercise.. In conclusion, it seems that although exercise can trigger migraine attacks, regular exercise may have prophylactic effect on migraine frequency. This is most likely due to an altered migraine triggering threshold in persons who exercise regularly. However, the frequency and intensity of exercise that is required is still an open question, which should be addressed in future studies to delineate an evidence-based exercise program to prevent migraine in sufferers.

Topics: Brain-Derived Neurotrophic Factor; Calcitonin Gene-Related Peptide; Endocannabinoids; Exercise; Exercise Therapy; Humans; Migraine Disorders; Orexins

Migraine is a highly prevalent neurological pain syndrome, and its management is limited due to side effects posed by current preventive therapies. Calcitonin gene-related peptide (CGRP) plays a crucial role in the pathogenesis of migraine. In recent years, research has been dedicated to the development of monoclonal antibodies against CGRP and CGRP receptors for the treatment of migraine. This review will focus on the first US FDA-approved CGRP-receptor monoclonal antibody developed for the prevention of migraine: erenumab. Two Phase II trials (one for episodic migraine and one for chronic migraine) and two Phase III trials for episodic migraine have been published demonstrating the efficacy and safety of erenumab in the prevention of migraine.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide; Treatment Outcome

Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine.. To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose.. Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12.. Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded.. Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8).. The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose.. Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2).. Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.. clinicaltrials.gov Identifier: NCT02629861.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Double-Blind Method; Drug Administration Schedule; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Migraine Disorders; Young Adult

Topics: Action Potentials; Aminocaproic Acid; Animals; Calcitonin Gene-Related Peptide; Circular Dichroism; Fluoresceins; Fluorescent Dyes; Humans; Male; Mice; Migraine Disorders; Protein Structure, Secondary; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin Gene-Related Peptide; Vasodilator Agents

Some variables have been proposed as predictors of efficacy of OnabotulinumtoxinA in chronic migraine patients, but data available are inconclusive. We aimed to analyse the influence of single nucleotide polymorphisms in the response to OnabotulinumtoxinA.. We included 156 female patients treated with OnabotulinumtoxinA accordingly to PREEMPT paradigm in three headache units. OnabotulinumtoxinA was offered to patients that had not responded to topiramate and at least one other preventative. Age at first procedure was 43.7 ± 11.8 years (16-74). Patients with a reduction of at least 50% in the number of migraine days after two OnabotulinumtoxinA procedures were considered as responders. We analysed 25 polymorphisms selected for their relevance regarding migraine pathophysiology and their association with migraine according to previously published genome-wide association studies. Genotyping was performed using KASP probes and a LightCycler-480 (Roche-Diagnostics). Allelic, genotypic frequencies and dominance/recesivity hypothesis of the allelic variants were compared between responders and non-responders by Fisher's exact test.. Response to treatment with OnabotulinumtoxinA was achieved in 120 patients (76,9%). Two polymorphisms showed differences: CALCA rs3781719, where allele C represents 26.9% in responders and 40.9% in non-responders (p = 0.007, OR = 3.11 (1.33-7.26)); and TRPV1 rs222749, where allele A represents 4.17% in responders and 12.5% in non-responders (p = 0.013, OR = 3.29 (1.28-8.43)). No significant differences in rest of polymorphisms or clinical or demographic variables were found.. Polymorphic variations of CALCA and TRPV1 genes might play a role as prognostic markers of efficacy of OnabotulinumtoxinA in chronic migraine female patients in our population.

Topics: Adolescent; Adult; Aged; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide; Chronic Disease; Female; Gene Frequency; Genome-Wide Association Study; Humans; Middle Aged; Migraine Disorders; Neuromuscular Agents; Polymorphism, Single Nucleotide; Prospective Studies; Topiramate; Treatment Outcome; TRPV Cation Channels; Young Adult

Specific prophylactic migraine treatments are urgently needed because of the unmet needs of many migraine patients. Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have recently shown efficacy in episodic and chronic migraine and will be available soon.

Topics: Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Molecular Targeted Therapy; Receptors, Calcitonin Gene-Related Peptide

To investigate both the relationship and underlying mechanism between miR-30a and migraine.. Peripheral blood samples were collected from migraine patients and healthy people to extract RNA for quantitative Real-time PCR (qRT-PCR). The relationship between mRNA expressions and patient data was analyzed by t-test. Target genes of miR-30a were predicted by the TargetScan. The binding of miR-30a to the target gene was verified by dual fluorescein reporter assay. The protein expression of calcitonin/alpha-CGRP gene (CALCA), the miR-30a target gene, was detected by Western blot.. Expression levels of miR-30a in peripheral blood of migraine patients were significantly lower than those of healthy controls detected by qRT-PCR, and the methylation level of miR-30a in promoter region was remarkably increased. In addition, expression levels of miR-30a were significantly decreased in patients with bilateral seizures, persistent pain and high pain index. CALCA was found to be the target gene of miR-30a via bioinformatics analysis. We verified that miR-30a degrades CALCA by dual-luciferase reporter assay. Western blot results showed that overexpression of miR-30a down-regulated the CALCA expression, and knockdown of miR-30a upregulated the CALCA expression.. Expression levels of miR-30a are significantly decreased in migraine patients and can relieve migraine through the degradation of CALCA.

Topics: Adolescent; Adult; Calcitonin Gene-Related Peptide; Female; Humans; MicroRNAs; Middle Aged; Migraine Disorders; Young Adult

Calcitonin gene-related peptide (CGRP) has been reported as elevated in chronic migraine. We aimed to validate the role of interictal serum CGRP concentration in peripheral blood samples as a biomarker of chronic migraine.. We prospectively recruited patients with episodic and chronic migraine and normal controls (NCs) in the Samsung Medical Center between August 2015 and May 2016. Blood samples were collected interictally from antecubital veins per prespecified protocol. Serum CGRP measurement was performed in the central laboratory by a single experienced technician blinded to clinical information. Migraine subtype, headache days in the previous month, and the presence and characteristics of headache at ±2 days of measurement were evaluated at every visit.. A total of 156 migraineurs (106 episodic and 50 chronic) and 27 NCs were recruited in this study. Compared to NCs (75.7 ± 20.07 pg/mL) and patients with episodic migraine (67.0 ± 20.70 pg/mL), patients with chronic migraine did not show an interictal elevation of serum CGRP levels (64.9 ± 15.32 pg/mL). Serum CGRP concentration was not associated with headache status (ictal vs. interictal), migraine subtype (migraine with vs. without aura), use of preventive or acute medications, and comorbid medication overuse. Higher serum CGRP concentration did not predict treatment response in patients with chronic migraine.. Serum CGRP concentration may not be a feasible biomarker for chronic migraine. Further validation is necessary before CGRP can be used in the clinical practice.

Topics: Adult; Biomarkers; Calcitonin Gene-Related Peptide; Chronic Disease; Feasibility Studies; Female; Follow-Up Studies; Headache; Humans; Male; Middle Aged; Migraine Disorders; Prospective Studies

Background Cranial autonomic parasympathetic symptoms (CAPS) appear in at least half of migraine patients theoretically as a result of the release of peptides by the trigemino-vascular system (TVS). Cranial pain pathways become sensitised by repeated episodes of TVS activation, leading to migraine chronification. Objective The objective of this article is to correlate the presence of CAPS with serum levels of vasoactive intestinal peptides (VIP) and calcitonin gene-related peptide (CGRP). Patients and methods Patients with chronic migraine (CM) were asked about the presence - during migraine attacks - of five CAPS, which were scored from 0 to 10 by using a quantitative scale. Serum VIP and CGRP levels were determined by ELISA. Results We interviewed 87 CM patients (82 females; mean age 44.7 ± 10.6 years). Seventeen had no CAPS, while 70 reported at least one CAPS. VIP levels ranged from 20.8 to 668.2 pg/ml (mean 154.5 ± 123.2). There was a significant positive correlation between scores in the CAPS scale and VIP levels (Spearman correlation coefficient = 0.227; p = 0.035). VIP levels were significantly higher in CM patients by at least one point in the scale vs those with 0 points ( p = 0.002). Analysing symptoms individually, VIP levels were numerically higher in those patients with symptoms, though they were significantly higher only in those patients with lacrimation vs those without it ( p = 0.013). There was no significant correlation between CGRP levels and the score in the CAPS scale. Conclusions Serum VIP, but not CGRP, levels seem to reflect the rate of activation of the parasympathetic arm of the TVS in migraine.

Topics: Adult; Aged; Autonomic Nervous System Diseases; Calcitonin Gene-Related Peptide; Female; Humans; Male; Middle Aged; Migraine Disorders; Vasoactive Intestinal Peptide; Young Adult

Background Migraine is much more common in females than in males, and occurrence is associated with changes in female sex hormones. Calcitonin gene-related peptide (CGRP) plays a key role in migraine, and variations in female sex hormones may affect CGRP sensitivity and/or production. Objectives Investigate repeatability, gender differences, influence of the menstrual cycle and of migraine on CGRP-dependent changes in dermal blood flow (DBF). Methods CGRP-dependent increases in DBF were assessed using laser Doppler perfusion imaging after topical application of 300 or 1000 µg capsaicin on the forearm of healthy subjects and migraine patients. Results In healthy males, DBF response did not vary over time and was comparable with DBF in male migraineurs. In healthy females, capsaicin-induced DBF responses to both doses of capsaicin were higher during menstruation compared to the late-secretory phase (p < 0.05); this menstrual cycle dependence was absent in female migraine patients. Compared to healthy subjects, female migraineurs displayed a higher DBF response both during menstruation and during the late-secretory phase (p < 0.05). Conclusions An increased capsaicin-induced, CGRP-mediated DBF response was observed during menstruation in healthy women, but in female migraine patients this increased response was not affected by the menstrual cycle.

Topics: Adult; Calcitonin Gene-Related Peptide; Capsaicin; Female; Humans; Laser-Doppler Flowmetry; Male; Menstrual Cycle; Migraine Disorders; Sensory System Agents; Skin; Vasodilation; Young Adult

Migraine is a common neurovascular brain disorder characterised by recurrent attacks of severe headache that may be accompanied by various neurological symptoms. Migraine is thought to result from activation of the trigeminovascular system followed by vasodilation of pain-producing intracranial blood vessels and activation of second-order sensory neurons in the trigeminal nucleus caudalis. Calcitonin gene-related peptide (CGRP) is a mediator of neurogenic inflammation and the most powerful vasodilating neuropeptide, and has been implicated in migraine pathophysiology. Consequently, genes involved in CGRP synthesis or CGRP receptor genes may play a role in migraine and/or increase susceptibility. This study investigates whether variants in the gene that encodes CGRP, calcitonin-related polypeptide alpha (CALCA) or in the gene that encodes a component of its receptor, receptor activity modifying protein 1 (RAMP1), are associated with migraine pathogenesis and susceptibility. The single nucleotide polymorphisms (SNPs) rs3781719 and rs145837941 in the CALCA gene, and rs3754701 and rs7590387 at the RAMP1 locus, were analysed in an Australian Caucasian population of migraineurs and matched controls. Although we find no significant association of any of the SNPs tested with migraine overall, we detected a nominally significant association (p=0.031) of the RAMP1 rs3754701 variant in male migraine subjects, although this is non-significant after Bonferroni correction for multiple testing.

Topics: Alleles; Calcitonin; Calcitonin Gene-Related Peptide; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Migraine Disorders; Polymorphism, Single Nucleotide; Protein Precursors; Receptor Activity-Modifying Protein 1

Migraine is a risk factor for ischemic stroke. Sterile vascular inflammation may develop during migraine attacks. This study aims to investigate procalcitonin (PCT) levels amongst migraine patients as they are important markers for infection and sepsis, but can also be found at elevated levels in various cases of inflammation.. Eighty adult migraine patients participated in our study. Patients were initially separated into two main groups; Group-1 consisted of 34 patients who had migraines during the attack period. Group-2 consisted of 46 patients during the period in-between attacks. Afterwards, patients were further divided into four subgroups based on their aura status; Group-1a Migraine without aura, 27 patients during attack period, Group-1b Migraine with aura, 7 patients during attack period, Group-2a Migraine without aura, 40 patients during the period in-between attacks, Group-2b Migraine with aura, 6 patients during the period in-between attacks.. Average PCT levels in patients during attack periods were found to be higher than the average PCT levels of patients during the period in-between attacks. These elevated levels were determined to be statistically significant(p<0.01). Serum PCT levels of the patients with migraine without aura during the attack period were significantly higher than those of patients during the period in-between attacks(p<0.01).. Based on significantly high levels of PCT, our results support the idea that sterile inflammation plays a role in migraine pathogenesis. Further studies are necessary to understand whether PCT is a marker for ischemic stroke risk in patients who go through frequent migraine attacks.

Topics: Adult; Calcitonin; Calcitonin Gene-Related Peptide; Disease Progression; Female; Humans; Immunoassay; Linear Models; Male; Middle Aged; Migraine Disorders; Protein Precursors; Time Factors

Migraine is a neurological disorder that is associated with increased levels of calcitonin gene-related peptide (CGRP) in plasma. CGRP, being one of the mediators of neurogenic inflammation and a phenomenon implicated in the pathogenesis of migraine headache, is thus suggested to have an important role in migraine pathophysiology. Polymorphisms of the CALCA gene have been linked to Parkinson's disease, ovarian cancer and essential hypertension, suggesting a functional role for these polymorphisms. Given the strong evidence linking CGRP and migraine, it is hypothesised that polymorphisms in the CALCA gene may play a role in migraine pathogenesis. Seemingly non functional intronic polymorphisms are capable of disrupting normal RNA processing or introducing a splice site in the transcript. A 16bp deletion in the first intron of the CALCA gene has been reported to be a good match for the binding site for a transcription factor expressed strongly in neural crest derived cells, AP-2. This deletion also eliminates an intron splicing enhancer (ISE) that may potentially cause exon skipping. This study investigated the role of the 16bp intronic deletion in the CALCA gene in migraineurs and matched control individuals. Six hundred individuals were genotyped for the deletion by polymerase chain reaction followed by fragment analysis on the 3130 Genetic Analyser. The results of this study showed no significant association between the intronic 16bp deletion in the CALCA gene and migraine in the tested Australian Caucasian population. However, given the evidence linking CGRP and migraine, further investigation of variants with this gene may be warranted.

Topics: Australia; Calcitonin; Calcitonin Gene-Related Peptide; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Migraine Disorders; Polymerase Chain Reaction; Polymorphism, Genetic; Protein Precursors

Olcegepant is the first potent and selective non-peptide antagonist of the calcitonin gene-related peptide 1 (CGRP1) receptor, a key modulator in neurogenic inflammatory pain. Under development by Boehringer Ingelheim GmbH, olcegepant is an intravenously formulated treatment for acute attacks of migraine. In preclinical studies, olcegepant attenuated arterial dilation induced by CGRP or electrical stimulation. In a phase II clinical trial, olcegepant reduced the severity of headache in 60% of migraine sufferers and met secondary endpoints including headache-free rate and rate of sustained response. Only mild-to-moderate transient adverse events were observed, with no adverse cardiovascular symptoms reported. The compound appears to be an effective anti-migraine medication that is well tolerated and does not display the vasoconstrictive effect that precludes the use of triptans and dihydroergotamine in certain patients. For a successful marketing of olcegepant, larger clinical trials and the development of an effective oral formulation will be necessary.

Topics: Analgesics; Animals; Calcitonin; Calcitonin Gene-Related Peptide; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dipeptides; Humans; Injections, Intravenous; Migraine Disorders; Molecular Structure; Patents as Topic; Piperazines; Protein Precursors; Quinazolines; Treatment Outcome