Calcitonin Gene-related Peptide Receptor Research Articles

A Drug-Drug Interaction Study to Evaluate the Impact of Rimegepant on OCT2- and MATE1-Mediated Transport of Metformin in Healthy Participants.

Rimegepant is a calcitonin gene-related peptide receptor antagonist approved for migraine treatment. This phase 1, open-label, single-center, fixed-sequence study evaluated the effect of rimegepant on the pharmacokinetics (PK) of metformin. Twenty-eight healthy participants received metformin 500mg twice daily from Days 1 to 4 and Days 7 to 10, and once daily on Days 5 and 11. Rimegepant, 75mg tablet, was administered once daily from Days 9 to 12. At pre-specified time points, plasma metformin concentration, serum glucose levels, and safety and tolerability were evaluated. A 16% increase in the area under the plasma metformin concentration-time curve (AUC) for 1 dosing interval (AUC0-τ,ss), a statistically insignificant increase in maximum and minimum steady-state metformin concentration (Cmax,ss and Cmin,ss), and a decrease in metformin renal clearance were observed on Day 11 following metformin-rimegepant coadministration compared with metformin alone; however, the changes were not clinically relevant. Additionally, coadministration of rimegepant with metformin did not induce clinically meaningful change in the maximum observed glucose concentration (Gmax) or AUCgluc compared with metformin alone. Overall, rimegepant and metformin coadministration did not result in clinically relevant changes in metformin PK, renal clearance, or the antihyperglycemic effects of metformin. Rimegepant is considered safe for use with metformin.

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist.

The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Mechanical and cold polymodality coexist in tactile peripheral afferents, and it's not mediated by TRPM8.

In the mammalian somatosensory system, polymodality is defined as the competence of some neurons to respond to multiple forms of energy (e.g., mechanical and thermal). This ability is thought to be an exclusive property of nociceptive neurons (polymodal C-fiber nociceptors) and one of the pillars of nociceptive peripheral plasticity. The current study uncovered a completely different neuronal sub-population with polymodal capabilities on the opposite mechanical modality spectrum (tactile). We have observed that several tactile afferents (1/5) can respond to cold in non-nociceptive ranges. These cells' mechanical thresholds and electrical properties are similar to any low-threshold mechano-receptors (LT), conducting in a broad range of velocities (Aδ to Aβ), lacking CGRP and TRPM8 receptors. Due to its density, cold-response range, speed, and response to injury (or lack thereof), we speculate on its role in controlling reflexive behaviors (wound liking and rubbing) and modulation of nociceptive spinal cord integration. Further studies are required to understand the mechanisms behind this neuron's polymodality, central architecture, and impact on pain perception.

Atogepant: Mechanism of action, clinical and translational science.

Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.

Ubrogepant: Mechanism of action, clinical and translational science.

In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene-related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval.

Calcitonin gene-related peptide receptor antagonism reduces motion sickness indicators in mouse migraine models.

Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.

Mediation of the JNC/ILC2 pathway in DBP-exacerbated allergic asthma: A molecular toxicological study on neuroimmune positive feedback mechanism

BackgroundDibutyl phthalate (DBP), a commonly used plasticizer, has been found to be strongly linked to a consistently high prevalence of allergic diseases, particularly allergic asthma. Previous animal experiments have demonstrated that exposure to DBP can worsen asthma by triggering the production of calcitonin gene-related peptide (CGRP), a neuropeptide in the lung tissue. However, the precise neuroimmune mechanism and pathophysiology of DBP-exacerbated allergic asthma with the assistance of CGRP remain unclear. ObjectiveThe present study was to investigate the potential pathophysiological mechanism in DBP-exacerbated asthma from the perspective of neural-immune interactions. Methods and resultsC57BL/6 mice were orally exposed to different concentrations (0.4, 4, 40 mg/kg) of DBP for 28 days. They were then sensitized with OVA and nebulized with OVA for 7 consecutive excitations. To investigate whether DBP exacerbates allergic asthma in OVA induced mice, we analyzed airway hyperresponsiveness and lung histopathology. To investigate the activation of JNC and TRPV1 neurons and the release of CGRP by JNC cells, we measured the levels of TRPV1 channels, calcium inward flow, and downstream neuropeptide CGRP. Results showed that TRPV1 expression, inward calcium flux, and CGRP levels were significantly elevated in the lung tissues of the 40DBP + OVA group, suggesting the release of CGRP by JNC cells. To counteract the detrimental effects of DBP mediated by CGRP, we employed olcegepant (also known as BIBN-4096), a CGRP receptor specific antagonist. Results revealed that 40DBP + OVA + olcegepant led to notable decreases in TRPV1, calcium inward flow, and CGRP expression in lung tissues compare with 40DBP + OVA, further supporting the efficacy of olcegepant. Additionally, we also conducted ILC2 flow sorting and observed that neuropeptide CGRP-activated ILC2 cells have a crucial role as key effector cells in DBP-induced neuroimmune positive feedback regulation. Finally, we examined the protein expression of CGRP, GATA3 and P-GATA3, and found that significant upregulations of CGRP and P-GATA3 in the 40DBP + OVA group, suggest that GATA3 acted as a key regulator of CGRP-activated ILC2. ConclusionThe aforementioned studies indicate that exposure to DBP can exacerbate allergic asthma, leading to airway inflammation. This exacerbation occurs through the activation of TRPV1 in JNC, resulting in the release of CGRP. The excessive release of CGRP further promotes the release of Th2 cytokines by inducing the activation of ILC2 through GATA phosphorylation. Consequently, this process contributes to the development of airway inflammation and allergic asthma. The increased production of Th2 cytokines also triggers the production of IgE, which interacts with FcεRI on JNC neurons, thereby mediating neuro-immune positive feedback regulation.

Effect of chronic intermittent hypoxia on ocular and intraoral mechanical allodynia mediated via the calcitonin gene-related peptide in a rat.

Obstructive sleep apnea, a significant hypoxic condition, may exacerbate several orofacial pain conditions. The study aims to define the involvement of calcitonin gene-related peptide (CGRP) in peripheral and central sensitization and in evoking orofacial mechanical allodynia under chronic intermittent hypoxia (CIH). Male rats were exposed to CIH. Orofacial mechanical allodynia was assessed using the eyeblink test and the two-bottle preference drinking test. The CGRP-immunoreactive neurons in the trigeminal ganglion (TG), CGRP-positive primary afferents projecting to laminae I-II of the trigeminal spinal subnucleus caudalis (Vc), and neural responses in the second-order neurons of the Vc were determined by immunohistochemistry. CGRP receptor antagonist was administrated in the TG. CIH-induced ocular and intraoral mechanical allodynia. CGRP-immunoreactive neurons and activated satellite glial cells (SGCs) were significantly increased in the TG and the number of cFos-immunoreactive cells in laminae I-II of the Vc were significantly higher in CIH rats compared to normoxic rats. Local administration of the CGRP receptor antagonist in the TG of CIH rats attenuated orofacial mechanical allodynia; the number of CGRP-immunoreactive neurons and activated SGCs in the TG, and the density of CGRP-positive primary afferent terminals and the number of cFos-immunoreactive cells in laminae I-II of the Vc were significantly lower compared to vehicle-administrated CIH rats. An increase in CGRP in the TG induced by CIH, as well as orofacial mechanical allodynia and central sensitization of second-order neurons in the Vc, supported the notion that CGRP plays a critical role in CIH-induced orofacial mechanical allodynia.

Receptor activity-modifying proteins of adrenomedullin (RAMP2/3): Roles in the pathogenesis of ARDS.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by widespread inflammation and pulmonary edema. Adrenomedullin (AM), a bioactive peptide with various functions, is expected to be applied in treating ARDS. Its functions are regulated primarily by two receptor activity-modifying proteins, RAMP2 and RAMP3, which bind to the AM receptor calcitonin receptor-like receptor (CLR). However, the roles of RAMP2 and RAMP3 in ARDS remain unclear. We generated a mouse model of ARDS via intratracheal administration of lipopolysaccharide (LPS), and analyzed the pathophysiological significance of RAMP2 and RAMP3. RAMP2 expression declined with LPS administration, whereas RAMP3 expression increased at low doses and decreased at high doses of LPS. After LPS administration, drug-inducible vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2−/−) showed reduced survival, increased lung weight, and had more apoptotic cells in the lungs. DI-E-RAMP2−/− mice exhibited reduced expression of Epac1 (which regulates vascular endothelial cell barrier function), while RAMP3 was upregulated in compensation. In contrast, after LPS administration, RAMP3−/− mice showed no significant changes in survival, lung weight, or lung pathology, although they exhibited significant downregulation of iNOS, TNF-α, and NLRP3 during the later stages of inflammation. Based on transcriptomic analysis, RAMP2 contributed more to the circulation-regulating effects of AM, whereas RAMP3 contributed more to its inflammation-regulating effects. These findings indicate that, while both RAMP2 and RAMP3 participate in ARDS pathogenesis, their functions differ distinctly. Further elucidation of the pathophysiological significance and functional differences between RAMP2 and RAMP3 is critical for the future therapeutic application of AM in ARDS.

The role of CGRP monoclonal antibodies in migraine treatment – efficacy, safety, and perspectives for the future: a systematic review

Background: Migraine is a widespread headache disorder occurring in every age group. It is divided into two types: chronic and episodic migraine. Many medications have been used in its treatment over the years with different degrees of effectiveness. In recent years, more attention has been given to the role of CGRP monoclonal antibodies for treatment, which are CGRP ligand antibodies (fremanezumab, galcanezumab, eptinezumab) and a CGRP receptor antibody (erenumab).Aim of the study: This study aimed to analyze the efficacy and safety of using CGRP monoclonal antibodies in migraine treatment and discuss CGRP’s role in migraine pathogenesis. Both chronic and episodic migraines were subjects of interest.Material and methods: The search was conducted using the PubMed database. We analyzed articles published in the years 2017–2022. The used keywords were “Migraine”, “Monoclonal antibodies”, “CGRP”, and “Calcitonin gene-related peptide”.Results: The number of articles found depended on the keyword used (“migraine” - 1875 results, “monoclonal antibodies” - 12173 results, “CGRP” - 352 results, and “calcitonin gene-related peptide” - 461 results). A total of 31 articles were quoted in this review. Positive results for treating migraines with CGRP ligand antibodies (fremanezumab, galcanezumab, eptinezumab) and CGRP receptor antibody (erenumab) were observed.Conclusions: The use of CGRP ligand and receptor antibodies seems promising for migraine therapy due to their relatively mild side effects and high efficiency.

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment.

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.

Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA

Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome. This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18-75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020). Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63-2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo. Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome. AbbVie.

A Comprehensive Review of the Mechanism, Efficacy, Safety, and Tolerability of Ubrogepant in the Treatment of Migraine.

Ubrogepant is an innovative medication designed for the acute treatment of migraine, a debilitating neurological condition that profoundly impairs quality of life, productivity, and social interactions. This comprehensive review assesses the efficacy, safety, tolerability, and mechanism of action of ubrogepant through a rigorous methodology, including an in-depth literature review from reputable databases like PubMed, Web of Science, Embase, Scopus, and Cochrane. Classified as a calcitonin gene-related peptide (CGRP) receptor antagonist, ubrogepant has emerged as a potential revolutionary medication for migraine treatment. CGRP is a peptide integral to migraine pathophysiology, and its blockade has demonstrated great therapeutic potential. Unlike triptans, known for their cardiovascular risks, ubrogepant lacks vasoconstrictive properties, making it a safer alternative for a broader patient population. Ubrogepant offers significant potential for pain relief, symptom reduction, and restoration of normal function during a migraine attack, and it outperforms placebo in terms of efficacy. It also presents favorable safety, with generally mild adverse drug events (ADEs), such as nausea, dizziness, and somnolence, similar to placebo effects. Consistent results from clinical trials confirm its tolerability, with minor ADEs and no safety alerts for the tested doses, indicating that ubrogepant is a safe and well-tolerated option for migraine treatment. As an effective oral medication, ubrogepant could be an alternative to traditional acute migraine treatments. Its benefits include a unique mechanism of action, rapid onset, and favorable safety profile. However, specific contraindications, such as hypersensitivity, severe hepatic impairment, concurrent use of CYP3A4 inhibitors, pregnancy or breastfeeding, and uncontrolled hypertension, require caution or avoidance of ubrogepant. Despite these limitations, ubrogepant signals a promising new direction in migraine therapeutics.

Impact of a reimbursement policy change on treatment with erenumab in migraine – a real-world experience from Germany

BackgroundMonoclonal antibodies (mAbs) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway are safe and effective treatments for migraine prevention. However, the high cost of these novel therapies has led to reimbursement policies requiring patients to try multiple traditional preventives before access. In Germany, a recent change in insurance policy significantly expanded coverage for the CGRP receptor mAb erenumab, enabling migraine patients who failed just one prior prophylactic medication to receive this mAb. Here, we compare the clinical response to treatment with erenumab in migraine patients treated using the old and new coverage policy.MethodsIn this retrospective cohort study, we included CGRP-mAb naïve patients with episodic or chronic migraine, who started erenumab at our headache center according to either the old or the new insurance policy and received at least 3 consecutive injections. Headache diaries and electronic documentation were used to evaluate reductions in monthly headache and migraine days (MHD and MMD) and ≥ 50% and ≥ 30% responder rates at month 3 (weeks 9–12) of treatment.ResultsWe included 146 patients who received erenumab according to the old policy and 63 patients that were treated using the new policy. At weeks 9–12 of treatment, 37.7% of the old policy group had a 50% or greater reduction in MHD, compared to 63.5% of the new policy group (P < 0.001). Mean reduction in MHD was 5.02 days (SD = 5.46) and 6.67 days (SD = 5.32, P = 0.045) in the old and new policy cohort, respectively. After propensity score matching, the marginal effect of the new policy on treatment outcome was 2.29 days (standard error, SE: 0.715, P = 0.001) more reduction in MHD, and 30.1% (SE: 10.6%, P = 0.005) increase in ≥ 50% response rate for MHD.ConclusionsStarting erenumab earlier in the course of migraine progression in a real-world setting may lead to a better response than starting after multiple failed prophylactic attempts. Continually gathering real-world evidence may help policymakers in deciding how readily to cover CGRP-targeted therapies in migraine prevention.

Sensory nerves, but not sympathetic nerves, promote reparative dentine formation after dentine injury via CGRP-mediated angiogenesis: An in vivo study.

Dental pulp is richly innervated by nerve fibres, which are mainly involved in the sensation of pain. Aside from pain sensation, little is known regarding the role of dental innervation in reparative dentine formation. We herein generated a mouse model of experimental dentine injury to examine nerve sprouting within the odontoblast and subodontoblastic layers and investigated the potential effects of this innervation in reparative dentinogenesis. Mouse tooth cavity model (bur preparation + etching) was established, and then nerve sprouting, angiogenesis and reparative dentinogenesis were determined by histological and immunofluorescent staining at 1, 3, 7, 14 and 28 days postoperatively. We also established the mouse-denervated molar models to determine the role of sensory and sympathetic nerves in reparative dentinogenesis, respectively. Finally, we applied calcitonin gene-related peptide (CGRP) receptor antagonist to analyse the changes in angiogenesis and reparative dentinogenesis. Sequential histological results from dentine-exposed teeth revealed a significant increase in innervation directly beneath the injured area on the first day after dentine exposure, followed by vascularisation and reparative dentine production at 3 and 7 days, respectively. Intriguingly, abundant type H vessels (CD31+ Endomucin+ ) were present in the innervated area, and their formation precedes the onset of reparative dentine formation. Additionally, we found that sensory denervation led to blunted angiogenesis and impaired dentinogenesis, while sympathetic denervation did not affect dentinogenesis. Moreover, a marked increase in the density of CGRP+ nerve fibres was seen on day 3, which was reduced but remained elevated over the baseline level on day 14, whereas the density of substance P-positive nerve fibres did not change significantly. CGRP receptor antagonist-treated mice showed similar results as those with sensory denervation, including impairments in type H angiogenesis, which confirms the importance of CGRP in the formation of type H vessels. Dental pulp sensory nerves act as an essential upstream mediator to promote angiogenesis, including the formation of type H vessels, and reparative dentinogenesis. CGRP signalling governs the nerve-vessel-reparative dentine network, which is mostly produced by newly dense sensory nerve fibres within the dental pulp.

Antinociceptive effect of the calcitonin gene-related peptide receptor antagonist BIBN4096BS in mice with bacterial cystitis.

Patients with urinary tract infections (UTIs) suffer from urinary frequency, urgency, dysuria, and suprapubic pain, but the mechanisms by which bladder afferents sense the presence of uropathogens and encode this information is not well understood. Calcitonin gene-related peptide (CGRP) is a 37-mer neuropeptide found in a subset of bladder afferents that terminate primarily in the lamina propria. Here, we report that the CGRP receptor antagonist BIBN4096BS lessens lower urinary tract symptoms and prevents the development of pelvic allodynia in mice inoculated with uropathogenic Escherichia coli (UPEC) without altering urine bacterial loads or the host immune response to the infection. These findings indicate that CGRP facilitates the processing of noxious/inflammatory stimuli during UPEC infection. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria, a region where afferent fibers containing CGRP terminate, that expresses the canonical CGRP receptor components Calcrl and Ramp1. We propose that these fibroblasts, in conjunction with CGRP+ afferents, form a circuit that senses substances released during the infection and transmit this noxious information to the central nervous system.NEW & NOTEWORTHY Afferent C fibers release neuropeptides including calcitonin gene-related peptide (CGRP). Here, we show that the specific CGRP receptor antagonist, BIBN409BS, ameliorates lower urinary tract symptoms and pelvic allodynia in mice inoculated with uropathogenic E. coli. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria that expresses the canonical CGRP receptor. Our findings indicate that CGRP contributes to the transmission of nociceptive information arising from the bladder.

Evaluation of the effect of erenumab on migraine-specific questionnaire in patients with chronic and episodic migraine.

Erenumab is a fully human anti-canonical calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. The Migraine-Specific Quality-of-Life Questionnaire (MSQ) is a 14-item patient-reported outcome instrument that measures the impact of migraine on health-related quality of life. Erenumab data from four phase II/III clinical trials were used to develop an item response theory (IRT) model within a nonlinear mixed effects framework, (i) evaluate the MSQ item information with respect to patient disability, (ii) characterize the longitudinal progression of the MSQ, and (iii) quantify the effect of erenumab on the MSQ in patients with migraine. The majority (80%) of information was found to be contained in 9 out of 14 items, extending the current knowledge on the reliability of the MSQ as a psychometric tool. Simulations across three MSQ domains show significant improvement from baseline, exceeding minimally important differences. Overall, the IRT model platform developed herein allows for systematic quantification of the effect of erenumab on the MSQ in patients with migraine.

Efficacy and safety of monoclonal antibodies targeting CGRP in migraine prevention. GRADE tables elaborated by the ad hoc working group of the International Headache Society.

Grading of Recommendations, Assessment Development and Evaluation (GRADE) tables were created using a standardized and independent assessment of the efficacy and side effects of treatments with monoclonal antibodies (mAb) against calcitonin gene-related peptide (CGRP) or the CGRP receptor for the prevention of migraine. We hope to provide support for author groups writing national or regional treatment or management guidelines for migraine prevention. We formulated patient/population, intervention, comparison and outcomes (PICO) questions for the efficacy and safety of mAb against CGRP or the CGRP-receptor for the prevention of migraine attacks. We performed a systematic literature research for randomized studies with eptinezumab, erenumab, fremanezumab and galcanezumab and a pooled analysis was done, using RevMan 5.4 software. For dichotomous outcomes we used risk ratio, and for continuous outcomes we used the mean difference to compare and summarize the evidence between groups. The evidence across studies, for each outcome, except serious adverse events, was assessed using GRADE evidence tables. Additionally, we report the serious adverse effects in the tables of the characteristics of the studies. All mAb are superior to placebo for the reduction in monthly migraine days (days in which a headache consistent with migraine occurred) in participants with episodic and chronic migraine. There are no major differences between the mAb. The GRADE evidence summary tables provided will support author groups to write treatment guidelines for the prevention of migraine with mAb.

Preventive and abortive treatment of migraine with traditional drugs. The state of the art

IntroductionMigraine is a chronic neurological disease, with a prevalence of 15.2% in Brazil. It is 2.2 times more prevalent in women, predominantly in the 18-50 age group. Its pathophysiological mechanism is still not completely understood. Possibly headache attacks and symptoms are associated with cortical spreading depression, the trigeminovascular system, neurogenic inflammation, vasodilation and genetic vulnerability.ObjectiveThis is a narrative review of preventive and abortive treatment of migraine.CommentMigraine treatment is based on three pillars: patient education, treatment of the disease itself or prevention of attacks, and acute treatment of headache attacks. The therapeutic classes of traditional drugs used in migraine prevention are beta-blockers, tricyclic antidepressants, calcium channel antagonists or blockers, and anticonvulsant neuromodulators. Specific drugs used in the treatment of headache attacks are triptans or serotonergic 5-HT1B/1D receptor agonists, ditans or 5-HT1F receptor agonists, and gepants or CGRP receptor antagonists.ConclusionTraditional drugs used in the preventive or abortive treatment of migraine are considered to be effective. Through modulation of the disease mechanisms, there is a reduction in the frequency, intensity and duration of headache attacks, and also in the disability caused by the headache. All this to improve the quality of life of patients. The therapeutic classes of traditional drugs used in migraine prevention are beta-blockers, tricyclic antidepressants, antagonists or blockers of calcium channels and anticonvulsant neuromodulators. Specific drugs used in the treatment of headache attacks are triptans or serotonergic 5-HT1B/1D receptor agonists,ditans or 5-HT1F receptor agonists, and gepants or CGRP receptor antagonists.

Evaluation of Vestibular Functions in a Case of Vestibular Migraine With Successful Treatment With Erenumab.

This is the first report of vestibular examinations before and after the successful treatment of vestibular migraine (VM), a common cause of recurrent vertigo, with calcitonin gene-related peptide (CGRP) receptor inhibitor. We evaluated a 42-year-old female with VM and concomitant probable Meniere's disease, whose headache and dizziness have improved promptly with the administration of erenumab, a CGRP receptor inhibitor. The sensorineural hearing loss in pure-tone audiometry, dysfunctions shown in vestibular examinations (cervical and ocular vestibular evoked myogenic potentials), and mild endolymphatic hydrops shown in gadolinium-enhanced inner ear magnetic resonance imaging, all in the right ear, revealed no change compared with those observed before treatment. This case suggests that VM may be treated by blocking CGRP in the trigeminal ganglion, which suppresses the effects on the vestibular nucleus; herein, no effects were observed in the inner ear despite the clear amelioration of dizziness.