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Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance., Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research., Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations., Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients., (© 2024. The Author(s).)

Background: The role of beta calcitonin gene-related peptide (beta-CGRP) in gastrointestinal tract is obscure, but experimental models suggest an effect on the homeostasis of the intestinal mucosa. We measured beta-CGRP circulating levels in a large series of subjects with a recent diagnosis of inflammatory bowel disease (IBD), in order to assess the potential role of this neuropeptide in IBD pathogenesis., Methods: Morning serum beta-CGRP levels were measured by ELISA (CUSABIO, China) in 96 patients recently diagnosed of IBD and compared with those belonging from 50 matched healthy controls (HC) and 50 chronic migraine (CM) patients., Results: Beta-CGRP levels were lower in patients with IBD (3.1 ± 1.9 pg/mL; 2.9 [2.4-3.4] pg/mL) as compared to HC (4.7 ± 2.6; 4.9 [4.0-5.8] pg/mL; p < 0.001) and to CM patients (4.6 ± 2.6; 4.7 [3.3-6.2] pg/mL; p < 0.001). Beta-CGRP levels in CM were not significantly different to those of HC (p = 0.92). Regarding IBD diagnostic subtypes, beta-CGRP levels for ulcerative colitis (3.0 ± 1.9pg/mL; 2.5 [2.1-3.4] pg/mL) and Crohn's disease (3.3 ± 2.0 pg/mL; 3.2 [2.4-3.9] pg/mL) were significantly lower to those of HC (p < 0.01 and p < 0.05, respectively) and CM (p < 0.01 and p < 0.05, respectively)., Conclusions: We have found a significant reduction in serum beta-CGRP levels in patients with a recent diagnosis of all kinds of IBD as compared to two control groups without active intestinal disease, HC and CM, which may suggest a role for this neuropeptide in the pathophysiology of IBD. Our data indicate a protective role of beta-CGRP in the homeostasis of the alimentary tract., (© 2024. The Author(s).)

Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud's phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere's trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s 2 )] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury., (© 2024. The Author(s).)

Objective: To observe the clinical effect of nape seven needles combined with pressing moxibustion for cervical vertigo (CV)., Methods: A total of 70 patients with CV were randomized into an observation group and a control group, 35 cases in each group. In the observation group, nape seven needles combined with pressing moxibustion was delivered, once a day, 6 times a week, for consecutive 2 weeks. In the control group, betahistine hydrochloride tablet and aceclofenac dispersible tablet were given orally, for 2 weeks and 3 days respectively. Before and after treatment, the evaluation scale for cervical vertigo (ESCV) score was observed, the plasma levels of neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene related peptide (CGRP) were detected, the hemorheologic and hemodynamic indexes were measured, and the clinical efficacy was evaluated after treatment in the two groups., Results: After treatment, the scores of dizziness, daily life and work ability, psychological and social adaptability, and headache, as well as the total scores of ESCV were increased compared with those before treatment ( P <0.01, P <0.05) in the two groups, and the score and total score of neck and shoulder pain of ESCV was increased compared with that before treatment ( P <0.01) in the observation group; each sub-item score and total score of ESCV in the observation group were higher than those in the control group ( P <0.01, P <0.05). After treatment, the plasma levels of NPY and ET-1 were decreased compared with those before treatment ( P <0.01), while the plasma levels of CGRP were increased compared with those before treatment ( P <0.01, P <0.05) in the two groups; the plasma levels of NPY and ET-1 in the observation group were lower than those in the control group ( P <0.01), the plasma level of CGRP in the observation group was higher than that in the control group ( P <0.01). After treatment, the whole blood high shear viscosity, plasma viscosity and whole blood low shear viscosity were decreased compared with those before treatment ( P <0.01, P <0.05), the mean velocity of basilar artery (BA), left vertebral artery (LVA) and right vertebral artery (RVA) were increased compared with those before treatment ( P <0.05) in the two groups; the whole blood high shear viscosity, plasma viscosity and whole blood low shear viscosity in the observation group were lower than those in the control group ( P <0.01), and the mean velocity of BA, LVA and RVA in the observation group were higher than those in the control group ( P <0.05). The total effective rate in the observation group was 91.4% (32/35), which was superior to 71.4% (25/35) in the control group ( P <0.05)., Conclusion: Nape seven needles combined with pressing moxibustion can effectively alleviate the clinical symptoms, and improve the hemorheology and hemodynamics in CV patients.

Objectives: In this study, we aimed to investigate the regulatory mechanism of transcranial ultrasound stimulation (TUS) on nitroglycerin-induced migraine in mice., Materials and Methods: The experiment was divided into four groups, namely, the normal saline control group (n = 9), ultrasound stimulation control group (n = 6), nitroglycerin-induced migraine group (n = 9), and ultrasound stimulation group (n = 9). The behavior, blood oxygen metabolism, and brain rhythm distribution of the four groups were analyzed., Results: We found that after TUS, the movement time and speed of mice with migraine are modulated to those of the control groups, and the number of head scratching and grooming events is significantly reduced. TUS increased the deoxygenated hemoglobin, and the power of the 4-to-40 Hz frequency band of local field potentials in the cortex of migraine mice. TUS also decreased the expression of plasma calcitonin gene-related peptide and cortical c-Fos protein., Conclusions: Ultrasound stimulation can regulate brain rhythm and blood oxygen metabolism and reduce migraine symptoms in mice. The regulatory mechanism may be related to reducing calcitonin gene-related peptide in blood vessels., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Transcranial direct current stimulation (tDCS) has been suggested as an alternative treatment option for migraine. The present study aimed to evaluate the efficacy of tDCS on clinical outcomes in addition to calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide 38 (PACAP-38) levels in individuals with menstrual-related migraine (MRM) for the first time., Materials and Methods: In this parallel study, 58 female patients between the ages of 18 and 45 years, including 36 with MRM and 22 with nonmenstrual migraines (nMM), were recruited. Sessions of 2-mA 20-minute anodal tDCS were administered over the left dorsolateral prefrontal cortex within three consecutive days (1:1 active and sham stimulation). Migraine attack frequency, severity, analgesic usage, CGRP, and PACAP-38 levels of the patients were evaluated before and one month after tDCS., Results: After tDCS, in the active group compared with the sham group, the frequency (p = 0.031), the severity of attacks (p = 0.003), the number of days with headache (p = 0.004), and the analgesic usage (p = 0.024) were all decreased. In both MRM and nMM groups, the frequency and severity of attacks and analgesic usage were decreased in those receiving active stimulation (p < 0.001 for each). CGRP and PACAP-38 levels were no different in the active group and the sham group after tDCS., Conclusions: tDCS was shown to be efficacious in migraine prophylaxis and a valuable option for migraine and MRM treatment. The absence of changes in serum CGRP and PACAP-38 levels suggests that tDCS efficacy may stem from distinct cerebral electrophysiological mechanisms., Competing Interests: Conflict of Interest The authors report no conflict of interest., (Copyright © 2024 International Neuromodulation Society. All rights reserved.)

Background: Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure often presenting with chronic migraine-like headache. Calcitonin gene-related peptide (CGRP) plays an important pathophysiological role in primary headaches such as migraine, whilst its role in IIH has not yet been established., Methods: This longitudinal exploratory study included patients with IIH, episodic migraine (EM) in a headache-free interval and healthy controls (HC). Blood samples were collected from a cubital vein and plasma CGRP (pCGRP) levels were measured by standardized ELISA., Results: A total of 26 patients with IIH (mean age 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m 2 [IQR 30.0-41.4]), 30 patients with EM (mean age 27.6 years [7.5], 66.7% female) and 57 HC (mean age 25.3 years [5.2], 56.1% female) were included. pCGRP levels displayed a wide variation in IIH as well as in EM and HC on a group-level. Within IIH, those with migraine-like headache had significantly higher pCGRP levels than those with non-migraine-like headache (F (2,524)  = 84.79; p < 0.001) and headache absence (F (2,524)  = 84.79; p < 0.001) throughout the observation period, explaining 14.7% of the variance in pCGRP levels. CGRP measurements showed strong intraindividual agreement in IIH (ICC 0.993, 95% CI 0.987-0.996, p < 0.001). No association was found between pCGRP levels and ophthalmological parameters., Conclusions: Although interindividual heterogeneity of pCGRP levels is generally high, migraine-like headache seems to be associated with higher pCGRP levels. CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH., (© 2024. The Author(s).)

Background: Migraine affects 11-15% of people worldwide, and the calcitonin gene-related peptide (CGRP) is released during the migraine attack, producing pulsating pain of migraine. Also, lacosamide reacts with collapsin-response mediator protein 2, preventing its phosphorylation and leading to the inhibition of CGRP release in the trigeminal system., Objective: The primary outcome was the difference in the serum level of CGRP-LI after three months of treatment with either lacosamide and ibuprofen or ibuprofen alone in episodic migraine patients. The secondary outcomes were assessing safety and efficacy of lacosamide in episodic migraine patients., Methods: We conducted an open-label randomized controlled trial on episodic migraine patients aged 10-55 years diagnosed according to (ICHD-3) in Kafr El-Sheikh University Hospital, Egypt. We assessed serum levels of CGRP-LI before and three months after treatment in our two groups, the lacosamide, and the control groups. We also assessed the side effects of treatment in each group, the percentage of patients who achieved ≥ 50% reduction in the migraine monthly days (MMD) frequency and the percentage of patients who achieved pain freedom within 2 h in ≥ 4 of 5 attacks in each group., Results: 200 episodic migraine patients completed the study. There was a statistically significantly higher reduction in the serum CGRP-LI level in the lacosamide group compared with the control group. In addition, lacosamide was well tolerated by patients. Also, the lacosamide group had statistically significant higher percentage of patients who achieved ≥ 50% reduction in the migraine monthly days (MMD) frequency and pain freedom within two hours in ≥ 4 of 5 attacks with P-values 0.002, 0.02 respectively., Conclusion: The daily use of lacosamide 50 mg Bid for three months in episodic migraine patients was associated with a significant reduction in serum CGRP-LI, better clinical outcomes regarding frequency and duration of migraine attacks, and was well tolerated by patients. These results were derived from an open-label pilot study that needed to be thoroughly investigated by a large-scale, randomized, double-blinded, placebo-controlled study., Trial Registration:  We registered our trial on ClinicalTrials.gov, named after "The Lacosamide's Effect on Calcitonin Gene-related Peptide in Migraine Patients," and with a clinical trial number (NCT05632133)-August 8, 2023., (© 2024. The Author(s).)

Background: Migraine lacks biomarkers that can trace the biological pathways of the disease and predict the effectiveness of treatments. Monoclonal antibodies targeting calcitonin gene-related peptide pathway - including erenumab - offer the opportunity of investigating potential migraine biomarkers due to their specific mechanism of action in preventing both episodic (EM) and chronic (CM) migraine. Our study aims at evaluating the expression levels of circulating microRNAs (miRNAs) according to migraine type, before and after treatment with erenumab and based on treatment response, in order to identify miRNAs with potential role as epigenetic biomarkers., Methods: The study included women aged 25-50 years with EM or CM treated with erenumab according to clinical indications. MiRNAs expression levels were assessed before (baseline) and after a 16-week treatment with erenumab, 140 mg every four weeks (post-treatment). An extensive miRNAs profiling was performed by qRT-PCR in small, pooled groups of ≤ 8 women each, classified according to migraine frequency (EM and CM) and the degree of response to erenumab. The expression levels of selected miRNAs were also validated using single miRNA assays in each woman with EM and CM., Results: During the study, 36 women with migraine (19 with EM and 17 with CM) out of 40 who were initially screened, performed the assessment of miRNA expression at baseline and post-treatment, Erenumab treatment significantly improved migraine burden in both EM and CM. MiRNA profiling revealed differential expression levels of a wide set of miRNAs (hsa-let-7d-3p, hsa-miR-106b-3p, hsa-miR-122-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-16-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-25-3p, hsa-miR-29b-2-5p, hsa-miR-326, miR-363-3p, hsa-miR-424-5p, hsa-miR-485-3p, hsa-miR-532-5p, hsa-miR-543, hsa-miR-629-5p, hsa-miR-660-5p, hsa-miR-92a-3p) depending on treatment response. Among them, single miRNA assays confirmed the progressive decrease of hsa-miR-143-3p expression levels in relation to increasing response to erenumab in women with EM (7 with low, 6 with medium, and 6 with high response; p = 0.02). Additionally, single assays showed higher hsa-miR-34a-5p and hsa-miR-382-5p expression levels at baseline in women with CM compared with those with EM (p = 0.0002 and p = 0.0007, respectively), as well as their expression level decrease in women with CM from baseline to follow-up (p = 0.04 and p = 0.02, respectively)., Conclusions: Our study suggests that targeting the CGRP pathway in migraine changes the expression levels of certain miRNAs. These miRNA levels are linked to the levels of response to CGRP receptor blockage. Future research challenges include assigning specific functions to the modulated miRNAs to unravel pathways modulated by the disease and the treatment., Trial Registration: The study was registered in clinicaltrials.gov with code NCT04659226 and in the Novartis database with code CAMG334AIT05T., (© 2024. The Author(s).)

The inhibition of endocannabinoid hydrolysis by enzymatic inhibitors may interfere with mechanisms underlying migraine-related pain. The dual FAAH/MAGL inhibitor AKU-005 shows potent inhibitory activity in vitro. Here, we assessed the effect of AKU-005 in a migraine animal model based on nitroglycerin (NTG) administration. Male rats were treated with AKU-005 (0.5 mg/kg, i.p.) or vehicle 3 h after receiving NTG (10 mg/kg, i.p.) or NTG vehicle. One hour later, rats were subjected to the open field test followed by the orofacial formalin test. At the end of the test, we collected serum samples for assessing calcitonin gene-related peptide (CGRP) levels as well as meninges, trigeminal ganglia, and brain areas to assess mRNA levels of CGRP and pro-inflammatory cytokines, and endocannabinoid and related lipid levels. AKU-005 reduced NTG-induced hyperalgesia during the orofacial formalin test but did not influence NTG-induced changes in the open field test. It significantly reduced serum levels of CGRP, CGRP, and pro-inflammatory cytokine mRNA levels in the meninges, trigeminal ganglia, and central areas. Surprisingly, AKU-005 caused no change in endocannabinoids and related lipids in the regions evaluated. The present findings suggest that AKU-005 may have anti-migraine effects by reducing CGRP synthesis and release and the associated inflammatory events. This effect, however, does not seem mediated via an interference with the endocannabinoid pathway., Competing Interests: The authors declare no conflicts of interest.

Background: Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology, and post-traumatic headache (PTH) frequently presents with migraine-like features. Despite several clinical similarities, few studies have explored CGRP in PTH and concussion. This study investigates serum CGRP levels in patients with persistent post-concussion symptoms (PPCS), including PTH., Methods: This cohort study was based on serum samples from individuals aged 18-30 years with PPCS who participated in a previously published randomized controlled trial of a non-pharmacological intervention. The primary outcome was serum CGRP concentrations, determined at baseline before randomization and at follow-up 7 months later, using an enzyme-linked immunosorbent assay (ELISA). CGRP levels at baseline were compared with healthy anonymous blood donors in the same age group., Results: Baseline serum samples were collected from 86 participants with PPCS. The participants were most often female (78%) and migraine-like headache was the most frequent headache phenotype (74%). Serum CGRP levels were higher in participants with PPCS than in 120 healthy individuals (median: 158.5 pg/mL vs. 76.3 pg/mL, p = 0.050). A stratified analysis revealed that females with PPCS had a fivefold higher median than healthy females (166.3 pg/mL vs. 32.1 pg/mL, p = 0.0006), while no differences were observed in males (p = 0.83). At follow-up, CGRP levels decreased with a median change of  - 1.3 pg/mL (95% confidence interval:  - 17.6-0, p = 0.024)., Discussion: Elevated serum levels of CGRP in patients with PPCS and a decrease over time suggest an involvement of CGRP in PTH/PPCS. If confirmed in other studies, it could pave the way for CGRP-targeted therapies, which could have clinical significance., (© 2024. The Author(s).)

Background: Calcitonin gene-related peptide (CGRP) is the most promising candidate to become the first migraine biomarker. However, literature shows clashing results and suggests a methodological source for such discrepancies. We aimed to investigate some of these methodological factors to evaluate the actual role of CGRP as biomarker., Methods: Previous to the experimental part, we performed a literature review of articles measuring CGRP in migraine patients. Using our 399 bio-bank sera samples, we performed a series of experiments to test the validity of different ELISA kits employed, time of sample processing, long-term storage, sampling in rest or after moderate exercise. Analysis of in-house data was performed to analyse average levels of the peptide and the effect of sex and age., Results: Literature review shows the high variability in terms of study design, determination methods, results and conclusions obtained by studies including CGRP determinations in migraine patients. CGRP measurements depends on the method and specific kit employed, also on the isoform detected, showing completely different ranges of concentrations. Alpha-CGRP and beta-CGRP had median with IQR levels of 37.5 (28.2-54.4) and 4.6 (2.4-6.4)pg/mL, respectively. CGRP content is preserved in serum within the 24 first hours when samples are stored at 4°C after clotting and immediate centrifugation. Storages at -80°C of more than 6 months result in a decrease in CGRP levels. Moderate exercise prior to blood extraction does not modulate the concentration of the peptide. Age positively correlates with beta-CGRP content and men have higher alpha-CGRP levels than women., Conclusions: We present valuable information for CGRP measurements in serum. ELISA kit suitability should be tested prior to the experiments. Alpha and beta-CGRP levels should be analysed separately as they can show different behaviours even within the same condition. Samples can be processed in a 24-h window if they have been kept in 4°C and should not be stored for more than 6 months at -80°C before assayed. Patients do not need to rest before the blood extraction unless they have performed a high-endurance exercise. For comparative studies, sex and age should be accounted for as these parameters can impact CGRP concentrations., (© 2024. The Author(s).)

Background and Objective: Endometriosis (EM) involves the peripheral nervous system and causes chronic pain. Sensory nerves innervating endometriotic lesions contribute to chronic pain and influence the growth phenotype by releasing neurotrophic factors and interacting with nearby immune cells. Calcitonin gene-related peptide (CGRP), a pain-signaling neurotransmitter, has a significant role. This study examines the effect of Dienogest (DNG), a hormone therapy used for managing EM -related pain, on serum CGRP levels in EM patients., Materials and Methods: The Visual Analog Scale (VAS) assessed pain in diagnosed EM., Individuals: Serum samples were obtained to measure CGRP concentration. Participants received a 2 mg/day oral dose of DNG for six months as prescribed treatment. Additional serum samples were collected after this period to measure CGRP levels., Results: In the EM group, 6.7%, 33.3%, and 20% had ovarian EM, ovarian plus uterosacral, and ovarian plus bladder, respectively. The EM group showed higher CGRP serum levels than the control group (80.53 ± 16.13 vs. 58.55 ± 6.93, P < 0.0001). Still, after drug administration, CGRP serum levels significantly decreased compared to pre-treatment levels (69.66 ± 11.53 vs. 80.53 ± 16.13, P < 0.05). The EM group showed higher pain compared to the control group (7.93 ± 1.58 vs. 0.13 ± 0.35, P < 0.0001), but after drug administration, pain significantly decreased compared to pre-treatment levels (1.00 ± 2.00 vs. 7.93 ± 1.58, P < 0.05)., Conclusion: DNG administration reduces pain and serum CGRP levels in EM patients, offering the potential for innovative treatments and tailored options. Understanding neurotransmitter roles and drug effects can aid in discovering more effective modulators for these pathways., (© 2024. The Author(s).)

Colorectal cancer is one of the most widespread types of cancer that still causes many deaths worldwide. The development of new diagnostic and prognostic markers, as well as new therapeutic methods, is necessary. The calcitonin gene-related peptide (CGRP) neuropeptide alongside its receptor calcitonin receptor-like receptor (CRLR) could represent future biomarkers and a potential therapeutic target. Increased levels of CGRP have been demonstrated in thyroid, prostate, lung, and breast cancers and may also have a role in colorectal cancer. At the tumor level, it acts through different mechanisms, such as the angiogenesis, migration, and proliferation of tumor cells. The aim of this study was to measure the level of CGRP in colorectal cancer patients' serum by enzyme-linked immunosorbent assay (ELISA) and determine the level of CGRP and CRLR at the tumor level after histopathological (HP) and immunohistochemical (IHC) analysis, and then to correlate them with the TNM stage and with different tumoral characteristics. A total of 54 patients with newly diagnosed colorectal adenocarcinoma were evaluated. We showed that serum levels of CGRP, as well as CGRP and CRLR tumor level expression, correlate with the TNM stage, with local tumor extension, the presence of lymph node metastasis, and distant metastasis, and also with the tumor differentiation degree. CGRP is present in colorectal cancer from the incipient TNM stage, with levels increasing with the stage, and can be used as a diagnostic and prognostic marker and may also represent a potentially new therapeutic target.

Objective: Medication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation., Materials and Methods: The study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels., Results: Serum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores., Conclusion: We have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH., (© 2024. The Author(s).)

Purpose: Even if migraine is not fatal, it is a common and challenging disease with adverse effects on individuals' lives. The lack of objective diagnostic tools causes delays in diagnosis and treatment initiation. The primary aim of this study is to reveal the diagnostic value of Calcitonin Gene-Related Peptide (CGRP) and Pentraxin-3 (PTX-3) in acute migraine. To this aim, we compared the serum CGRP and PTX-3 levels of migraine patients with acute attacks to those in healthy individuals., Material and Method: A total of 135 individuals (85 patients with migraine attacks with or without aura and 50 healthy controls) participated in the study. Serum CGRP and PTX-3 levels were measured with ELISA analysis. A p value less than 0.05 was considered significant., Results: Serum CGRP [146.70 (21.52-413.67) vs. 65.90 (3.80-256.60) pg/mL] and PTX-3 levels [12.71 (0.62-33.97) vs. 1.01 (0.06-9.48) ng/mL] were higher in patients with migraine attack than the control group ( p  < 0.01 and p  < 0.01, respectively). ROC analysis showed that the cutoff value for serum CGRP was 121.39 pg/mL (AUC: 0.751, Sen:%61, Spe:%64) whereas the cutoff value for PTX-3 was 4,06 ng/mL (AUC:0.876, Sen:%73, Spe:%76). Serum CGRP levels were positively correlated with pain intensity. Serum CGRP and PTX-3 levels did not differ across gender groups and presence of aura in subgroup analysis., Conclusion: Patients with acute migraine attacks have higher serum CGRP and PTX-3 levels than controls. Both biomarkers show high potential for the diagnosis of a migraine attack.

Abstract: Ingestion of monosodium glutamate (MSG) causes headache, nausea, and craniofacial tenderness in healthy individuals. The present study explored whether MSG produces behavioural signs of headache, nausea, and changes in craniofacial sensitivity in rats. The behavior of male and female Sprague-Dawley rats was video recorded before and after intraperitoneal (i.p.) injections of MSG (1-1000 mg/kg), nitroglycerin (GTN, 10 mg/kg), or normal saline. Behaviors (grimace score, head-flicks, rearing, head scratches, facial grooming, lying-on-belly, and temporalis muscle region mechanical withdrawal threshold) were evaluated. Facial cutaneous temperature of the nose and forehead was measured before and after i.p. injections via infrared thermography. Plasma glutamate and calcitonin gene-related peptide concentrations after administration of 1000 mg/kg MSG were measured in anesthetized rats. Monosodium glutamate induced nocifensive, headache-like, and nausea-like behaviors in a dose-related manner but had no effect on mechanical threshold. Monosodium glutamate (1000 mg/kg) induced a significantly greater frequency of headache-like behavior in females but a longer duration of nausea-like behavior in males. Monosodium glutamate produced a prolonged increase in plasma glutamate and calcitonin gene-related peptide concentrations. Co-administration of the median effective dose of MSG (350 mg/kg) with GTN (10 mg/kg) amplified headache-like behaviors, induced significant craniofacial sensitivity, and produced increased nausea-like behaviour. Co-administration of sumatriptan or naproxen with MSG (1000 mg/kg) significantly attenuated MSG-induced nocifensive and headache-like behaviors. Our data suggest that systemic administration of MSG to rats induces behavioral correlates of headache and nausea. This model may offer another avenue for research on the mechanism and treatment of primary headache disorders such as migraine., (Copyright © 2022 International Association for the Study of Pain.)

Background: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation., Methods: All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T 0 ), at the end of the infusion (T 20 ), 10 min after the infusion (T 30 ), and 70 min after the infusion (T 90 )., Results: Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p  = 0.7074), tryptase ( p  = 0.6673), or histamine ( p  = 0.4792) remained unchanged during provoked attacks compared to attack-free patients., Conclusion: Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration : The study is registered at ClinicalTrials.gov (NCT03814226).

Introduction: Migraine is recognized as a complex neurological disorder that has imposed a social burden. We assessed the signaling pathways and molecular mechanisms based on the in silico analysis and predicted drug candidates by the biomedicine approach. Moreover, we evaluated high-intensity interval training and vitamin B12 + magnesium on women's migraine attacks and inflammatory status., Methods: This study computed differential gene expression in migraine syndrome and the dimension network parameters visualized by software. Moreover, we proposed the functional mechanism and binding energy of essential micronutrients on macromolecules based on drug discovery. In this clinical trial, 60 cases were randomized to four groups, including applied high-intensity interval training (HIIT), cases consumed supplementation vitamin B12 and magnesium (Supp), cases applied high-intensity interval training, and consumed supplementation (HIIT + Supp), and migraine cases for 2 months. Serum levels of calcitonin gene-related peptide (CGRP) were measured at baseline and at the end of the study. In addition, migraine disability assessment score (MIDAS), frequency, intensity, and duration were recorded before and during interventions., Results: In silico study revealed the association between inflammation signaling pathways and pathogenesis of migraine attacks as a remarkable pathomechanism in this disorder. Furthermore, serum concentrations of CGRP were significantly declined in the HIIT + Supp compared with other groups. In addition, MIDAS, frequency, intensity, and duration were reduced in the HIIT + Supp group compared with the other groups., Conclusion: We found that the synergistic effects of cobalamin and magnesium followed by regular exercise could silence the inflammation signaling pathway, and a combination of HIIT + Supp could ameliorate migraine pain., Trial Registration: This study was registered in the Iranian Registry of Clinical Trials; IRCT code: IRCT20170510033909N12. Approval Data: 2021/06/02., (© 2022. Fondazione Società Italiana di Neurologia.)

Objective: To investigate the effects of metoprolol succinate combined with Entresto (Sacubitril Valsartan Sodium Tablets) on cardiac function and coagulation function in patients with congestive heart failure (CHF)., Methods: About 120 patients with CHF treated from April 2018 to April 2021 were enrolled in our hospital. The patients were arbitrarily assigned into control group and study group. The control group was cured with metoprolol succinate sustained-release tablets, and the study group was cured with metoprolol succinate sustained-release tablets combined with Entresto. The curative effect, cardiac function, vascular endothelial function, oxidative stress, and coagulation function were compared., Results: First of all, we compared the general data, and there exhibited no difference in age, sex, course of disease, hypertension, coronary heart disease, diabetes, atrial fibrillation, and other general data ( P > 0.05). Second, we compared the clinical efficacy. The effective rate of the study group (98.33%) was higher (90.00%) ( P < 0.05). There exhibited no significant difference in cardiac function indexes before treatment, but after treatment, LVEF increased, LVESD and LVEDD decreased, LVESD and LVEDD in the study group were lower, and LVEF in the study group was higher ( P < 0.05). Before treatment, there exhibited no significant difference in vascular endothelial function. However, the levels of CGRP and ET increased and the level of NO decreased, and the level of NO in the study group was lower, while the levels of CGRP and ET in the study group were higher after treatment ( P < 0.05). There exhibited no significant difference in oxidative stress indexes before treatment, however, the levels of GSH-Px and SOD increased and the levels of MDA decreased after treatment, while the level of MDA in the study group was lower, while the levels of GSH-Px and SOD in the study group were higher ( P < 0.05). Finally, we compared the indexes of blood coagulation function. There exhibited no significant difference before treatment, but after treatment, the levels of APTT, PT, and FIB decreased, and the levels of APTT, PT, and FIB in the study group were lower ( P < 0.05)., Conclusion: Clinical practice demonstrated that LVESD and LVEDD decreased and LVEF increased after treatment with Entresto combined with metoprolol in CHF patients, which can effectively facilitate cardiac function and vascular endothelial function, reduce oxidative stress reaction, and improve blood coagulation indexes, suggesting that Entresto combined with metoprolol can improve ventricular remodeling with good safety., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yuanyuan Ding et al.)

This study determined prognostic factors by comparing clinico-bacterial factors based on significant elevated serum procalcitonin levels in patients with suspected bloodstream infection (BSI). We retrospectively analyzed the medical records of 1,052 patients (age ≥16 years) with fever (temperature ≥38°C) and serum procalcitonin levels of ≥2.0 ng/mL, and blood culture results. The optimal cutoff value of the significant elevation of procalcitonin was determined using the minimum P-value approach. Clinico-bacterial factors were analyzed per the procalcitonin levels, and significant independent factors for short-term survival were investigated in 445 patients with BSI. Patients with suspected BSI were aged, on average, 72.3 ± 15.1 years, and the incidence of positive blood culture was 42.3%; and the 14-day survival was 83.4%. Procalcitonin ≥100 ng/mL was the most significant predictor for survival. Multivariate analysis in patients with suspected BSI showed that estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 and procalcitonin ≥100 ng/mL were significant independent unfavorable prognostic factors. Microorganisms were similar between patients with procalcitonin level 2-99 ng/mL (n=359) and those with ≥100 ng/mL (n=86). Multivariate analysis in patients with BSI showed that eGFR <30 mL/min/1.73 m 2 , procalcitonin ≥100 ng/mL, and primary infectious foci were significant independent prognostic factors. Patients with foci in the gastrointestinal tract and respiratory system had unfavorable 14-day survival. In conclusions, eGFR <30 mL/min/1.73 m 2 and procalcitonin ≥100 ng/mL were significant independent unfavorable prognostic factors for suspected BSI. Primary infectious foci (gastrointestinal tract and respiratory system) were associated with unfavorable short-term survival in patients with positive blood culture., Competing Interests: There are no potential conflicts of interest to declare, with regard to the research, authorship, and publication of this article.

Background: Early cervical lymph node (LN) metastasis is an important cause of poor survival in patients with medullary thyroid cancer (MTC). This study evaluated whether the preoperative serum calcitonin level in combination with ultrasonographic features of MTC can be used to assess the LN status as well as predict the risk of metastasis in patients with MTC., Methods: We retrospectively analyzed the clinical data of 95 patients with MTC, and a nomogram model was constructed and validated. Using integrated database analysis of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), we mined pathways wherein CALCA is involved, identified calcitonin-related genes, and analyzed their functions., Results: Correlation analysis revealed a significant association between the infiltrating range, diameter, calcification, blood flow, the preoperative serum calcitonin level, and metastasis. The metastasis risk-prediction model showed great accuracy in determining the risk of metastasis in MTC (area under the curve of the receiver operating characteristic [ROC] curve: 0.979 [95% confidence interval 0.946-1.000]). Decision curve analysis (DCA) showed that the model has excellent clinical utilization potential. Significantly, CALCA , the mRNA for calcitonin, was highly expressed in thyroid cancer tissues and associated with the cytokine-cytokine receptor and neuroactive ligand-receptor interaction pathways as well as the cell-adhesion molecules. ROC curve indicated that the CNTFR , CD27 , GDF6 , and TSLP genes, which are related to the cytokine-cytokine receptor interaction pathway, could indicate the risk of metastasis in MTC., Conclusions: The preoperative serum calcitonin level, in combination with ultrasonographic features, can be used to predict the risk of metastasis in patients with MTC and constitute a noninvasive accurate method for preoperative diagnosis of MTC., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yi Fan et al.)

Objective: Although perineural invasion (PNI) is well-known to be correlated with and able to predict lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC), the clinical and molecular correlation between PNI and LNM has not been elucidated, and preoperative biomarkers for LNM prediction in OSCC are urgently needed., Materials and Methods: The correlation between PNI and LNM was retrospectively evaluated using a cohort of 218 patients diagnosed with OSCC. Candidate neuropeptides were screened based on TCGA database and verified via immunohistochemistry and Western blot analyses. ELISA was used to detect calcitonin gene-related peptide (CGRP) in patient plasma. In vitro assays were used to explore the effects of CGRP on OSCC cells., Results: OSCC patients with PNI had a higher incidence of LNM (69.86% vs. 26.2%, P < 0.0001, n = 218). CGRP expression was upregulated in the PNI niche and in metastatic lymph nodes, and was correlated with poor overall survival of OSCC patients. Preoperative plasma CGRP levels were higher in OSCC patients (n = 70) compared to healthy donors (n = 60) (48.59 vs. 14.58 pg/ml, P < 0.0001), and were correlated with LNM (P < 0.0001) and PNI (P = 0.0002). Preoperative plasma CGRP levels alone yielded an AUC value of 0.8088 to predict LNM, and CGRP levels combined with preoperative T stage reached an AUC value of 0.8590. CGRP promoted proliferation and migration abilities of OSCC cells, which could be antagonized by either pharmacological or genetic blockade of the CGRP receptor., Conclusions: The neuropeptide CGRP links PNI and LNM in OSCC, and preoperative plasma CGRP levels can be used to predict LNM in OSCC., (© 2021. The Author(s).)

We studied the effect of CCK-8 on BP and blood content of CGRP in rats with hypertension caused by fructose or inhibition of NO synthase with L-NAME. The decrease in the CGRP content was found during the development of fructose-induced hypertension, but not L-NAME-caused hypertension. Administration of CCK-8 to fructose-fed animals reduced BP and increased the content of CGRP. In rats with hypertension caused by NO deficit, CCK-8 lowered BP, but did not affect the content of CGRP. These findings suggest that CGRP mediates the hypotensive effect of CCK-8 in fructose-induced hypertension, but not in NO-deficient hypertension., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)