Calcitonin Gene-related Peptide Research Articles

Prevention of Episodic Migraine Headache Using Pharmacologic Treatments in Outpatient Settings: A Clinical Guideline From the American College of Physicians.

The American College of Physicians (ACP) developed this clinical guideline for clinicians caring for adults with episodic migraine headache (defined as 1 to 14 headache days per month) in outpatient settings. ACP based these recommendations on systematic reviews of the comparative benefits and harms of pharmacologic treatments to prevent episodic migraine, patients' values and preferences, and economic evidence. ACP evaluated the comparative effectiveness of the following interventions: angiotensin-converting enzyme inhibitors (lisinopril), angiotensin II-receptor blockers (candesartan and telmisartan), antiseizure medications (valproate and topiramate), β-blockers (metoprolol and propranolol), calcitonin gene-related peptide (CGRP) antagonist-gepants (atogepant or rimegepant), CGRP monoclonal antibodies (eptinezumab, erenumab, fremanezumab, or galcanezumab), selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (fluoxetine and venlafaxine), and a tricyclic antidepressant (amitriptyline). ACP used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to analyze the effects of pharmacologic treatment on the following outcomes: migraine frequency and duration, number of days medication was taken for acute treatment of migraine, frequency of migraine-related emergency department visits, migraine-related disability, quality of life and physical functioning, and discontinuations due to adverse events. In addition, adverse events were captured through U.S. Food and Drug Administration medication labels and eligible studies. In this guideline, ACP makes recommendations for clinicians to initiate monotherapy for episodic migraine prevention in nonpregnant adults in the outpatient setting as well as alternative approaches if initial treatments are not tolerated or result in an inadequate response. All 3 ACP recommendations have conditional strength and low-certainty evidence. Clinical considerations provide additional context for physicians and other clinicians.

Enhancing Stability and Bioavailability of Peptidylglycine Alpha-Amidating Monooxygenase in Circulation for Clinical Use

Peptidylglycine alpha-amidating monooxygenase (PAM) is the only enzyme known to catalyze C-terminal amidation, a final post-translational modification step essential for the biological activity of over 70 bioactive peptides, including adrenomedullin (ADM), calcitonin gene-related peptide (CGRP), amylin, neuropeptide Y (NPY), and others. Bioactive (amidated) peptide hormones play crucial roles in various physiological processes and have been extensively explored as therapeutic compounds in clinical and preclinical research. However, their therapeutic viability is limited due to their short half-life and, in most cases, the need for prolonged infusion to maintain effective concentrations. PAM itself has also been considered as a therapeutic compound aiming to increase the level of amidated peptide hormones; however, similarly to peptide hormones, PAM’s rapid degradation limits its utility. Here, we present a strategy to enhance PAM stability and bioavailability through PEGylation, significantly extending the enzyme’s half-life in circulation assessed in healthy rats. Furthermore, single subcutaneous (s.c.), intramuscular (i.m.), or intraperitoneal (i.p.) administration of PEGylated PAM resulted in a sustained increase in circulating amidating activity, with peak activity observed at 12–24 h post-bolus administration. Notably, amidating activity remained significantly elevated above baseline levels for up to seven days post-administration, with no observable adverse effects. These findings highlight PEGylated PAM’s potential as a viable therapeutic compound.

Comparative Effectiveness of Pharmacologic Treatments for the Prevention of Episodic Migraine Headache: A Systematic Review and Network Meta-analysis for the American College of Physicians.

Various treatments for preventing episodic migraine are available. To evaluate the comparative effectiveness and harms of pharmacologic prevention of episodic migraine, focusing on treatments already determined to be superior to placebo. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception until April 2024. Randomized trials evaluating selected efficacious pharmacologic treatments in adults with episodic migraine. Selection was done independently by 2 reviewers. Data were extracted by 1 reviewer and checked by a second. Risk of bias and certainty of the evidence were assessed using the Cochrane Risk of Bias tool and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, respectively. Sixty-one studies (20 680 patients) evaluating 16 treatments were included. Nineteen studies had low risk of bias. All selected treatments were deemed efficacious against placebo on the basis of previous systematic reviews. In network meta-analyses, calcitonin gene-related peptide antagonist monoclonal antibodies (CGRP-mAbs) probably resulted in fewer discontinuations due to adverse events than topiramate (risk difference, -16.2% [95% CI, -18.4% to -12.8%]; moderate-certainty evidence), and CGRP-mAbs may result in less migraine-related disability and improved quality of life compared with gepants (mean differences, -4.12 [CI, -9.30 to 1.05] and 2.25 [CI, -0.85 to 5.34], respectively; low-certainty evidence). For other outcomes and comparisons, there was moderate- or low-certainty evidence of no clinically important differences, uncertain evidence, or no evidence. Limited literature was available to determine the minimal important differences. The number of head-to-head comparisons of treatments was limited. No high-certainty evidence favored one pharmacologic treatment for prevention of episodic migraine over another. Evidence was mostly insufficient or of low certainty. American College of Physicians. (PROSPERO: CRD42023414305).

Shift from chronic to episodic migraine frequency in a long-term phase 3 study of galcanezumab

BackgroundChronic migraine (CM) is a highly disabling form of migraine in which patients have ≥ 15 headache days per month, of which at least 8 have the features of migraine. Galcanezumab is a monoclonal antibody to calcitonin gene-related peptide which is approved for the preventive treatment of migraine. Ability to convert patients from chronic migraine frequency to episodic migraine (EM) frequency is a clinically relevant and desirable outcome when prescribing preventive treatments to patients with CM.MethodsPatients aged 18–65 years with an ICHD-3β diagnosis of CM were randomized 2:1:1 to receive monthly injections of placebo (N = 558), galcanezumab 120 mg with a 240-mg loading dose (N = 278), or galcanezumab 240 mg (N = 277) during a 3-month double-blind period of the phase 3 REGAIN trial. Patients could subsequently enter a 9-month open-label extension in which they received galcanezumab 120 mg or 240 mg/month per investigator’s discretion. In this post-hoc analysis, we assessed the percentages of patients who shifted to EM (< 8 migraine headache days or < 15 headache days/month), low frequency EM (LFEM; <8 migraine headache days/month), and very low frequency EM (VLFEM; <4 migraine headache days/month) for at least 3 consecutive months. Double-blind percentage comparisons versus placebo represent modeled estimates from raw rates.ResultsAt baseline, patients had a mean of 19.4 migraine headache days per month (SD = 4.5) and 21.4 headache days per month (SD = 4.1). During the 3-month double-blind treatment period, a greater percentage of galcanezumab-treated patients shifted to EM frequency and maintained it across all 3 months (31.5%) than did placebo-treated patients (19.8%, p < 0.001). Among galcanezumab-treated patients across the entire 12-month trial, 65.1% shifted from CM to EM frequency, with 44.2% shifting to LFEM and 21.5% shifting to VLFEM for ≥ 3 consecutive months. Proportions of patients shifting from CM to EM frequency for ≥ 3 consecutive months and until last patient visit were: 55.0% to EM; 33.4% to LFEM; 13.9% to VLFEM.ConclusionThese results suggest that galcanezumab helped a majority of patients convert from chronic to episodic migraine frequency over the course of this 12-month study.Trial registrationClinicaltrials.gov NCT02614261, first registered November 25, 2015.

Myofascial trigger points therapy increases neck mobility and reduces headache pain in migraine patients – pilot study

BackgroundThis study aimed to evaluate the effects of Ischemic Compression Myofascial Trigger Points (IC-MTrPs) therapy, applied mainly to the upper trapezius muscle (UTM), on: [1] cervical spine range of motion (CS-ROM), and [2] headache characteristics in migraine patients. Reduced CS-ROM can further contribute to musculoskeletal strain and neurological discomfort in migraine sufferers. The application of IC-MTrPs therapy is of particular interest because it targets these trigger points, potentially normalizing muscle tone and improving local blood flow, which may alleviate pain and restore mobility.DesignA case series employing a repeated-measures design; pilot study.MethodsFifty-three adult female migraine patients were classified into three groups: episodic migraine without aura (MO, n = 31), episodic migraine with aura (MA, n = 15), and chronic migraine (CM, n = 7). Patients underwent seven sessions of IC-MTrPs therapy targeting the shoulder and neck muscles. Assessments were conducted across five sessions: pre-therapy (baseline), post-1st therapy, post-4th therapy, post-7th therapy, and at a 1-month follow-up. Outcome measures included: CS-ROM (assessed using an accelerometer system), subjective headache pain intensity (evaluated via the Visual Analog Scale (VAS)), and calcitonin gene-related peptide (CGRP) concentrations.ResultsCS-ROM for horizontal rotation and forward flexion improved significantly at the 1-month follow-up compared to pre-therapy (baseline) (P < 0.05). Headache intensity during a migraine attacks, as well as headache frequency and duration, significantly decreased at post-7th therapy compared to baseline across all patients (P < 0.05). The highest CGRP concentrations were recorded in CM patients (240.73 ± 79.51 ng/ml). While no significant changes in CGRP levels were observed in patients with MO, CGRP concentration in patients with MA increased significantly at the 1-month follow-up compared to baseline, rising from 151.70 ± 50.85 ng/ml to 176.17 ± 77.21 ng/ml. In patients with CM, the therapy did not result in statistically significant changes in CGRP levels, although reductions in headache frequency and intensity were noted.ConclusionsIC-MTrPs therapy proved effective in increasing CS-ROM and alleviating headache characteristics in all migraine subtypes. However, no significant changes in CGRP levels were observed. Distinct characteristics and responses among different migraine subtypes highlight the need for tailored therapeutic approaches.Trial registrationThe study protocol was retrospectively registered on December 2, 2022, as a clinical trial in the international clinical trial database ClinicalTrials.gov (identifier: NCT05646160). Clinical trial number: not applicable.

Abstract TP391: CGRP Monoclonal Antibody Does Not Exacerbate Stroke Outcomes in Mice

Background: Calcitonin gene-related peptide (CGRP) is a potent vasodilator that plays a role in migraine. Monoclonal antibodies targeting CGRP, such as fremanezumab, is now widely used for migraine prevention. However, inhibition of CGRP system may also lead to vasoconstriction, raising concerns about whether the long-term treatment with these antibodies in migraine patients might increase the risk of stroke or worsen outcomes if a stroke occurs while taking these medications. Here, we aimed to investigate whether fremanezumab exacerbates stroke outcomes in a mouse model of ischemic stroke. Methods: Two middle cerebral artery occlusion (MCAO) models were used: a 12-minute occlusion simulating a transient ischemic attack (TIA) and a 60-minute occlusion representing a conventional stroke model. Fremanezumab was administered intraperitoneally at either 2 days or 7 days before MCAO induction in both models; one cohort received treatment 28 and 7 days before MCAO. On day 2 after reperfusion, brain tissues were harvested for TTC staining to evaluate infarct volume. Neurological function was assessed using a neuro score and corner test. Additionally, an angiogram using black ink was performed to visualize cerebral vasculature, and vessel diameters were measured to determine the impact of fremanezumab on vascular dimensions. Results: Angiographic arterial diameters in the fremanezumab arm did not differ from the saline arm, suggesting that fremanezumab does not cause vasoconstriction. In the TIA model, the fremanezumab group exhibited a trend towards increased infarct incidence and volume and hemorrhagic transformation, although these did not reach statistical significance. Additionally, there were no substantial changes in neurological scores and the corner test. In the 60-minute MCAO model, no significant changes or trends were observed in infarct volume or other outcomes between the two treatment arms. Outcomes were similar when fremanezumab was administered 2 or 7 days before MCAO. Conclusion: Despite previous concerns that long-term use of fremanezumab might exacerbate stroke risk by promoting vasoconstriction, our findings do not support this hypothesis and suggest that fremanezumab does not worsen stroke outcomes in these models. These findings have important implications for the management of stroke risk in patients using fremanezumab for migraine prevention, suggesting that it may be used with confidence regarding its impact on stroke risk.

Left superior cervical ganglia lymph node mimicry and its role in rat ventricular arrhythmias following myocardial infarction.

Sympathetic overactivation may lead to severe ventricular arrhythmias (VAs) post-myocardial infarction (MI). The superior cervical ganglion (SCG) is an extracardiac sympathetic ganglion which regulates cardiac autonomic tone. We aimed to investigate the characteristics and functional significance of SCG on neuro-cardiac communication post-MI. Constructed MI rat model by left anterior descending coronary artery ligation, and electrophysiological, SCG sympathetic nerve activity testing, echocardiography and histology study were performed. The proteins and gene expression were detected using RNA-seq, spatial transcriptomics, quantitative PCR, and western blotting. The SCG neuronal remodeling was recognized by significant increase in adrenergic tyrosine hydroxylase (TH) (+) neurons and decrease in neuronal size. Top differentially expressed genes enriched in pro-inflammatory profile and nerve regulatory factor in left SCG (LSCG) post-MI. Interleukin (IL)-1β and IL-6 increased significantly at Day 3, ahead of nerve growth factor (NGF) which peaked at Day 7 post-MI. Spatial transcriptomics further identified the relativity of TH enrichment with macrophages and cytokines. Therapeutic LSCG-ectomy successfully triggered cardiac denervation and improved VA vulnerability. Eventually, cardiac denervation attenuated macrophage/mast cell infiltration at para-infarct regions, thus improved cardiac dysfunction. Mechanism study revealed that genetic knockdown of NGF receptor trkA in LSCG reversed sympathetic remodeling and cardiac inflammation, which may be partially mediated by substance P and calcitonin gene-related peptide (CGRP). Extracardiac sympathetic LSCG remodeling participated in arrhythmogenesis and cardiac inflammation/function post-MI. NGF bridged neuro-immune crosstalk between pro-inflammatory shifting and sympathetic overdrive. Targeting LSCG modification facilitated cardiac protection and prevented VAs post-MI.

Revisiting substance P in migraine: a methodological approach inspired by anti-CGRP and anti-PACAP success

Substance P, previously dismissed as a therapeutic target for migraine due to the failure of neurokinin-1 receptor antagonists, warrants renewed attention. Building on the success of therapies targeting the calcitonin gene-related peptide (CGRP) system and pituitary adenylate cyclase-activating peptide (PACAP) in migraine prevention, which highlight the importance of targeting peptides, this proposal reexamines substance P as a mediator in migraine pathophysiology. Using an established methodological framework, migraine-inducing properties of substance P can be evaluated through randomized, double-blind, placebo-controlled crossover studies involving healthy volunteers and individuals with a history of migraine. This approach aims to establish proof of concept for substance P’s role in migraine, laying the groundwork for investigations with animal and cell-based models and advancing the development of innovative treatments for patients refractory to current therapies.

Evidence of Involvement of the Calcitonin Gene-Related Peptide in Restless Legs Syndrome.

Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by an urge to move the legs, often with unpleasant sensations, particularly during rest. Current treatments include iron supplementation, dopamine agonists, and opioids, but new therapeutic approaches are needed. The dysfunction of the A11 nucleus, which modulates dopaminergic transmission to the spinal cord, is thought to play a role in RLS pathophysiology. Calcitonin gene-related peptide (CGRP), which is involved in pain modulation, may interact with A11 pathways, suggesting a role in RLS. This study aimed to assess the involvement of CGRP in RLS by determining if CGRP-related proteins are overexpressed in RLS patients. A cross-sectional study was conducted with 17 drug-free RLS patients (mean age 55.8 years) and 17 age- and gender-matched controls. Serum samples were analyzed using liquid chromatography-parallel reaction monitoring-tandem mass spectrometry (LC-PRM-MS/MS) to identify and quantify CGRP-related proteins. Principal component analysis (PCA) was used to differentiate between groups. PCA showed clear differentiation between RLS and control groups. Among 13 identified CGRP-related proteins, 10 were dysregulated in RLS patients: 8 were upregulated, and 2 were downregulated, among them notable proteins such as S100A12, ADM, SRSF6, and ADM2. This study indicates the significant involvement of CGRP and related proteins in RLS. This suggests these proteins may play roles in various aspects of the disorder. Further research is required to validate these findings and explore their clinical implications, including development of new treatment options that specifically address CGRP pathways. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuropathic corneal pain following refractive surgery: risk factors, clinical manifestations, imaging and proteomic characteristics

Background/aimsTo identify the risk factors for neuropathic corneal pain (NCP) following corneal refractive surgery and to report its clinical manifestations, imaging and proteomic characteristics.MethodsThis 1 year prospective cohort study included...

Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials.

Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine. ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18-80 years with >1 year history of EM and 4-14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2-4 classes of oral preventives. PROGRESS included participants aged 18-80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1-4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1-4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1-2 and 4. The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23-0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29-0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43-0.93, p = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1-4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1-4 compared with placebo. Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM. ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137. This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.

Antimicrobial Neuropeptides and Their Receptors: Immunoregulator and Therapeutic Targets for Immune Disorders

The interaction between the neuroendocrine system and the immune system plays a key role in the onset and progression of various diseases. Neuropeptides, recognized as common biochemical mediators of communication between these systems, are receiving increasing attention because of their potential therapeutic applications in immune-related disorders. Additionally, many neuropeptides share significant similarities with antimicrobial peptides (AMPs), and evidence shows that these antimicrobial neuropeptides are directly involved in innate immunity. This review examines 10 antimicrobial neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), α-melanocyte stimulating hormone (α-MSH), ghrelin, adrenomedullin (AM), neuropeptide Y (NPY), urocortin II (UCN II), calcitonin gene-related peptide (CGRP), substance P (SP), and catestatin (CST). Their expression characteristics and the immunomodulatory mechanisms mediated by their specific receptors are summarized, along with potential drugs targeting these receptors. Future studies should focus on further investigating antimicrobial neuropeptides and advancing the development of related drugs in preclinical and/or clinical studies to improve the treatment of immune-related diseases.

Erenumab in a patient with persistent headaches after subarachnoid hemorrhage: A case report of an effective treatment.

A patient with persistent refractory headaches from aneurysmal subarachnoid hemorrhage was treated with monthly erenumab injections, a monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor. These injections decreased the frequency and severity of the patient's debilitating headaches from daily to once or twice per month with positive improvement in function and quality of life. To our knowledge, this is the first reported case in the literature of a patient with persistent post-subarachnoid hemorrhage headache that was successfully treated with an antibody against the CGRP receptor. This case report highlights the role of CGRP in post-subarachnoid hemorrhage headaches and the potential role for CGRP pathway-based therapies as an effective treatment.

Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in femalerats: which one to blame?

Sarcopenia and cancer cachexia are two life-threatening conditions often misdiagnosed. The skeletal muscle is one of the organs most adversely affected by these conditions, culminating in poor quality of life and premature mortality. In addition, it has been suggested that chemotherapeutic agents exacerbate cancer cachexia, as is the case of doxorubicin. Herein, we sought to investigate markers of inflammation and neuromuscular junction (NMJ) remodeling during aging and in response to cancer or cancer with chemotherapy. To address this, we utilized female rats across three age groups-young, adult, and old-to examine age-related changes, with old rats serving as a sarcopenia model. Additionally, a chemically-induced breast cancer (BCa) model was implemented in female adult rats, both without (adult BCa) or with doxorubicin administration (adult BCaDOX), to study cancer cachexia. The atrophy of the gastrocnemius muscle was observed in old, adult BCa and adult BCaDOX rats compared to adult ones. No signs of inflammation or NMJ impairment were observed in adult BCa or adult BCaDOX rats, except for the low levels of the subunit α1 of the acetylcholine receptor in adult BCaDOX rats compared to adult ones. In contrast, old rats presented high serum levels of interleukin 6, brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide compared to young rats. In the gastrocnemius muscle, BDNF levels were decreased in old rats compared to adult rats, suggesting impaired skeletal muscle regeneration upon age-induced damage. The BDNF muscle levels were inversely correlated with its levels in circulation in adult and old rats. Hence, this work highlights BDNF as a specific biomarker of age-induced skeletal muscle atrophy, at least, in the differential diagnosis against cancer- or cancer with chemotherapy-induced muscle wasting.

One-Year Compliance After Calcitonin Gene-Related Peptide Monoclonal Antibody Therapy for Migraine Patients in a Real-World Setting: A Multicenter Cross-Sectional Study

Background: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are a breakthrough migraine treatment, but long-term compliance under limited public insurance coverage has not been well known. This study explores one-year treatment patterns and outcomes of CGRP mAbs using real-world data. Methods: This multicenter retrospective study included migraine patients treated with CGRP monoclonal antibodies (CGRP mAbs) from July 2022 to June 2023. Treatment discontinuation was defined as a gap of over 60 days between injections. Among patients with 12 months of follow-up, adherence was measured using the Proportion of Days Covered (PDC), calculated as the ratio of days covered to the follow-up duration, with PDC ≥ 80% indicating good adherence. Efficacy was also assessed, defined as a ≥50% reduction in monthly headache days and acute medication use. Results: The study included 140 patients (mean age 44.6 ± 12.1 years; 82.9% female). Migraine without aura was predominant (93.6%), and 65.0% had chronic migraine. CGRP mAbs discontinuation occurred in 71.4% of patients, primarily due to headache improvement (22.9%) or lack of efficacy (15.0%). Among 81 patients with 12 months of follow-up, good adherence was observed in 40.7% of patients. Among these patients, 60.6% achieved a ≥50% reduction in monthly headache days, and 51.9% showed a ≥50% reduction in monthly acute medication use. Conclusions: More than two-thirds of patients discontinued the CGRP mAb within 1 year, so these findings emphasize the need for strategies to improve adherence and optimize follow-up plans to enhance patient support.

IL-6 Signalling to Responding T Cells Is Key to Calcitonin Gene-Related Peptide-Exposed Endothelial Cell Enhancement of Th17 Immunity During Langerhans Cell Antigen Presentation.

Calcitonin gene-related peptide (CGRP) biases Langerhans cell (LC) Ag presentation to CD4+ T cells towards Th17-type immunity through actions on endothelial cells (ECs). We now report further evidence that IL-6 signalling at responding T cells mediates this effect. This CGRP effect was absent with ECs from IL-6 KO mice. Exposure of LCs, but not T cells, to IL-6 enhanced IL-6 and IL-17A production and reduced IFN-γ in the T-cell response. Pretreatment of LCs with IL-6 receptor α-chain (IL-6Rα) antibodies prior to IL-6 exposure significantly inhibited these responses. However, T-cell pretreatment with an IL-6/IL-6Rα chimera mimicked the effect of IL-6 pretreatment of LCs on T-cell responses. When this experiment was performed in the presence of the ADAM17 and ADAM10 inhibitor TAPI-1 during LC pretreatment of LCs and during the Ag presentation culture, release of soluble IL-6Rα chains into the medium was very significantly reduced, but this did not affect levels of T-cell cytokine release. Interestingly, LC exposure to IL-6 significantly increased LC IL-6 expression. Furthermore, pretreatment of T cells with antibodies against the IL-6 receptor β-chain significantly inhibited the IL-6 effect. CGRP may stimulate ECs in lymphatics and/or lymph nodes to produce IL-6 which likely results in migrating LCs nonclassically presenting IL-6. Furthermore, we found that IL-6 induces IL-6 production by LCs, suggesting an autocrine amplification pathway for this effect.

Danggui niantong decoction attenuates synovial fibrosis through regulating PI3k/AKT signaling pathway.

Danggui Niantong Decoction (DGNTD) is a traditional Chinese medicine compound formula that has been demonstrated to possess efficacy in the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), as well as for dispelling moisture and relieving pain. As mentioned before, DGNTD is essential for synovial inflammation in RA. The primary features of the OA synovial membrane are low-grade inflammation, hyperplasia with enhanced fibroblast-like synoviocytes (FLS) proliferation, and fibrosis, which can cause pain and stiffness. However, it is still unknown how DGNTD functions in the OA synovium. Clarify the influence of DGNTD on OA synovium and investigate potential mechanisms of action. The principal constituents of DGNTD were detected using liquid chromatography-mass spectrometry (LC-MS) analysis. To evaluate the effect of DGNTD on synovial inflammation and fibrosis, a transforming growth factor beta (TGF-β)-stimulated rat FLS cell model and a rat OA animal model based on anterior cruciate ligament transection (ACLT) and partial medial meniscectomy (MMx) were employed. Our results showed that 322 components were detected using LC-MS. In vivo, DGNTD therapy reduced pain, synovial inflammation, and fibrosis. The therapy significantly reduced levels of pain-related molecules, specifically calcitonin gene-related peptide (CGRP) and inducible nitric oxide synthase (iNOS), as well as fibrotic markers, including alpha smooth muscle actin (α-SMA) and type III collagen alpha-1 (Col3a1), in the synovium. A proteomics study demonstrated that DGNTD decreased the fibrotic protein Col3a1. DGNTD reduced the mRNA expression of pro-inflammatory and fibrotic markers (tumor necrosis factor alpha (TNF-α), interleukin-1 beta(IL-1β), interleukin-6(IL-6), α-SMA, Col3a1and TGF-β) in TGF-β-induced FLS. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and validation results revealed that DGNTD inhibits synovial fibrosis via the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (AKT) signaling pathway. DGNTD partially relieves pain, synovitis, and synovial fibrosis by regulating the PI3K/AKT pathway. These findings provide fresh information about the underlying mechanisms and successful therapy of OA, as well as a theoretical and experimental foundation for the clinical management of OA using DGNTD.

Role of neurogenic inflammation in intervertebral disc degeneration.

In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.

Pharmacological differences and switching among anti-CGRP monoclonal antibodies: A narrative review.

Antibodies targeting either the calcitonin gene-related peptide (CGRP), such as galcanezumab, fremanezumab, and eptinezumab, or the receptor (erenumab) have been approved for the prevention of episodic and chronic migraine. Although widely used and generally effective, a proportion of patients discontinue treatment due to lack of efficacy. In both randomized controlled trials and observational studies, all anti-CGRP monoclonal antibodies (mAbs) have consistently demonstrated comparable efficacy and tolerability, suggesting a pharmacological class effect. However, differences in therapeutic targets, structure, and pharmacokinetic characteristics may influence their efficacy and safety differently. Therefore, in patients not achieving a clinically meaningful response with one anti-CGRP antibody, switching to a different antibody may be a viable option. This review examines the pharmacological characteristics and distinctions among anti-CGRP mAbs, highlighting their mechanisms of action and pharmacokinetic profiles, along with the clinical observational data of switching. Finally, we summarize suggestions from international guidelines.

Medication underuse in real-life practice: the impact of galcanezumab towards achieving very low frequency episodic migraine in a southeast Asian middle-income nation

BackgroundMigraine progression, particularly from episodic to chronic migraine (CM), increases disease burden and healthcare costs. Understanding the new concept of “Medication Underuse Headache” should encourage the health care provider to consider early intervention with calcitonin gene-related peptide (CGRP) monoclonal antibodies. Galcanezumab given early in the course of the disease, may prevent migraine chronification and have a robust response, moreso than when initiated in later stages of migraine. We aimed to determine the efficacy of galcanezumab in achieving very low-frequency episodic migraine (VLFEM) among patients with high-frequency episodic migraine (HFEM) and CM in a real world-setting in Thailand.MethodsA single-center, retrospective real-world, cohort study was conducted between 2023 and 2024. Adults aged 18 years or more who were diagnosed with HFEM or CM were included in this trial and categorized into two groups: galcanezumab and oral migraine preventive medication (OMPM). In the galcanezumab group, oral preventive medications were slowly tapered off within 3 months. The primary outcome was the differences in percentage of patients achieving VLFEM at months 3 and 6 between the two groups. Secondary outcomes included the differences in migraine class improvement, sustained response, and headache day reduction.ResultsA total of 62 patients (31 in each group) were included: median age was 36.5 (IQR: 29.0–48.0) and 82% were female. There were no significant differences in the baseline demographic features between the two groups. The cumulative incidence of patients achieving VLFEM was significantly higher among the galcanezumab group compared to OMPM group (45.2% vs. 19.4% at month 3 and 52.9% vs. 32.4% at month 6, p = 0.03). After 6 months of follow-up, patients with HFEM who received galcanezumab were significantly more likely to achieve any improvements in migraine class compared to those who received OMPM (92.9% vs. 46.7%, p = 0.01). Among 15 patients who achieved VLFEM at month 3, 81.8% (9/11) of those who received galcanezumab and 50.0% (2/4) of those who received OMPM were able to sustain VLFEM at month 6.ConclusionsThis study emphasizes the benefit of early anti-CGRP therapy initiation, especially in patients with fewer headache days, and highlights the need for accessible migraine-specific treatments in low- to middle-income countries.