Calcitonin gene-related peptide facilitates sensitization of the vestibular nucleus in a rat model of chronic migraine

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.

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Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the up-regulation of interleukin-6 and thermal hyperalgesia in a rat model of mononeuropathy

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.03856.x ◽

2006 ◽

Vol 98 (1) ◽

pp. 180-192 ◽

Cited By ~ 53

Author(s):

Weiya Ma ◽

Remi Quirion

Keyword(s):

Rat Model ◽

Interleukin 6 ◽

Thermal Hyperalgesia ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene

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Demonstration of calcitonin gene-related peptide immunoreactive axons contacting dynorphin A(1–8) immunoreactive spinal neurons in a rat model of peripheral inflammation and hyperalgesia

Brain Research ◽

10.1016/0006-8993(88)90213-2 ◽

1988 ◽

Vol 475 (1) ◽

pp. 168-172 ◽

Cited By ~ 42

Author(s):

Osamu Takahashi ◽

Richard J. Traub ◽

M.A. Ruda

Keyword(s):

Rat Model ◽

Calcitonin Gene Related Peptide ◽

Peripheral Inflammation ◽

Spinal Neurons ◽

Dynorphin A ◽

Related Peptide ◽

Calcitonin Gene ◽

Immunoreactive Axons

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Calcitonin gene-related peptide levels in tear fluid are elevated in migraine patients compared to healthy controls

Cephalalgia ◽

10.1177/0333102419856640 ◽

2019 ◽

Vol 39 (12) ◽

pp. 1535-1543 ◽

Cited By ~ 6

Author(s):

Katharina Kamm ◽

Andreas Straube ◽

Ruth Ruscheweyh

Keyword(s):

Chronic Migraine ◽

Trigeminal Nerve ◽

Plasma Concentrations ◽

Calcitonin Gene Related Peptide ◽

Tear Fluid ◽

Direct Access ◽

Healthy Controls ◽

Significant Group ◽

Related Peptide ◽

Calcitonin Gene

Background Calcitonin gene-related peptide (CGRP) released from trigeminal nerve fibres indicates trigeminal activation and has a key role in migraine pathophysiology. The trigeminal nerve directly innervates the eye. Therefore, in this study, we compared Calcitonin gene-related peptide in tear fluid of migraine patients and healthy controls. Methods Calcitonin gene-related peptide concentrations in tear fluid and plasma of 48 episodic and 45 chronic migraine patients and 48 controls were assessed using ELISA. Results Calcitonin gene-related peptide levels in tear fluid (0.94 ± 1.11 ng/ml) were ∼140 times higher than plasma concentrations (6.81 ± 4.12 pg/ml). Tear fluid CGRP concentrations were elevated in interictal migraine patients (1.10 ± 1.27 ng/ml, n = 49) compared to controls (0.75 ± 0.80 ng/ml, p = 0.022). There was no difference in tear fluid CGRP levels between interictal episodic and chronic migraine patients (episodic: 1.09 ± 1.47 ng/ml, n = 30 and chronic: 1.10 ± 0.89 ng/ml, n = 19) and no correlation of tear fluid CGRP levels with headache frequency in interictal patients (rho = 0.062, p = 0.674). Unmedicated ictal migraine patients had even more elevated tear fluid CGRP levels than interictal migraine patients (1.92 ± 1.84 ng/ml, n = 13, p = 0.102), while medicated ictal migraine patients had lower levels (0.56 ± 0.47 ng/ml, n = 25, p = 0.011 compared to interictal patients), which were undistinguishable from controls ( p = 0.609). In contrast to tear fluid, no significant group differences were found in plasma CGRP levels. Conclusion To the best of our knowledge, this study shows, for the first time, increased CGRP tear fluid levels in migraine patients compared to healthy subjects. Detection of calcitonin gene-related peptide in tear fluid is non-invasive, and likely allows a more direct access to CGRP released from the trigeminal nerve than plasma sampling.

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Leukocyte Apheresis Using a Fiber Filter Suppresses Colonic Injury Through Calcitonin Gene–Related Peptide Induction

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz303 ◽

2019 ◽

Vol 26 (5) ◽

pp. 709-719

Author(s):

Hiroshi Yamasaki ◽

Keiichi Mitsuyama ◽

Shinichiro Yoshioka ◽

Kotaro Kuwaki ◽

Ryosuke Yamauchi ◽

...

Keyword(s):

Bone Marrow ◽

Blood Flow ◽

Disease Activity ◽

Inflammatory Cytokines ◽

Rat Model ◽

Tissue Expression ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene ◽

Colonic Blood Flow

Abstract Background The aim of this study was to address whether the therapeutic effect of leukocytapheresis (LCAP) depends on calcitonin gene– related peptide (CGRP) induction. Methods An HLA-B27 transgenic rat model was treated with an LCAP column. The effects of LCAP on clinical, endoscopic, and histologic disease activity, the colony-forming ability of colony-forming unit (CFU)–granulocyte macrophages (GMs), colonic blood flow, and tissue expression of tumor necrosis factor (TNF)–α and CGRP were examined. Changes in the effects of LCAP after pretreatment with the CGRP antagonist CGRP8–37 were also observed. A dextran sulfate sodium–induced colitis rat model included treatment with CGRP, and the effect was assessed based on clinical, endoscopic, and histologic disease activity, colonic blood flow, the colony-forming ability of CFU-GMs, and tissue expression of inflammatory cytokines and CGRP receptor families. Results LCAP improved disease activity, enhanced colonic blood flow, and induced the bone marrow colony-forming ability of CFU-GMs with an increase in CGRP mRNA levels. These effects were abolished by pretreatment with CGRP8–37. The administration of CGRP suppressed colitis, promoting colonic blood flow, inducing bone marrow–derived cells, downregulating inflammatory cytokines, and upregulating receptor activity–modifying protein–1. The mRNA and protein levels of inflammatory cytokines in lipopolysaccharide-stimulated mononuclear cells were also decreased after CGRP treatment. Conclusions The therapeutic effects of LCAP depend on CGRP induction. CGRP can effectively suppress colitis through the downregulation of inflammatory events and upregulation of protective events.

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Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain

Cephalalgia ◽

10.1177/0333102419861726 ◽

2019 ◽

Vol 39 (14) ◽

pp. 1827-1837 ◽

Cited By ~ 10

Author(s):

Sarah L Christensen ◽

Steffen Petersen ◽

David Møbjerg Kristensen ◽

Jes Olesen ◽

Gordon Munro

Keyword(s):

Rat Model ◽

Time Course ◽

Calcitonin Gene Related Peptide ◽

Current Data ◽

Rodent Models ◽

Onset Of Action ◽

Related Peptide ◽

Pain Pathways ◽

Calcitonin Gene ◽

Cutaneous Hypersensitivity

Introduction Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405. Methods Cutaneous sensitivity to hind paw, and periorbital mechanical stimulation were used as surrogate markers of activation of relevant pain pathways in each respective model. Separate experiments were performed to identify the time-course of treatment response to olcegepant (1 mg/kg i.p.) and ALD405 (10 mg/kg i.p.). Results Olcegepant and ALD405 significantly alleviated cutaneous mechanical hypersensitivity in both models compared with corresponding control treatments (saline and IgG control antibody respectively). As expected, the duration of anti-nociceptive action obtained with ALD405 was considerably longer than that associated with olcegepant. Surprisingly, in the spontaneous rat model the onset of action of ALD405 occurred within just 4 hours after administration. Discussion The current data clearly show that calcitonin gene-related peptide-mediated signaling is critically involved in the manifestation of cutaneous hypersensitivity in distinct rodent models of migraine-like pain and emphasise their translational relevance. Moreover, the unexpected rapidity of onset observed for ALD405 supports i) a probable site of action outside the blood-brain barrier, and ii) a potential clinical utility of specific monoclonal calcitonin gene-related peptide antibodies in the abortive treatment of migraine.

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