Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies

Miller, Silke; Liu, Hantao; Warfvinge, Karin; Shi, Licheng; Dovlatyan, Mary; Xu, Cen; Edvinsson, Lars

doi:10.1016/j.neuroscience.2016.04.046

Cited by 60 publications

(58 citation statements)

References 74 publications

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“…136 In that study, binding to both postsynaptic and presynaptic sites were observed, but the CGRP receptor was predominantly expressed by second-order neurons of the TNC. 136 …”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 79%

“…63,66 Recent studies using antibodies that specifically recognize the CGRP-binding site, which was discovered by using a fusion protein of the extracellular domains of RAMP1 and CLR, showed binding to human TG neurons and human vascular smooth muscle cells of the meningeal vasculature. 136 More detailed examination of tissues obtained from cynomolgus monkeys confirmed the presence of the CGRP receptor on dural vascular smooth muscle cell, neurons, and satellite glial cells of the TG and TNC neurons. 136 In that study, binding to both postsynaptic and presynaptic sites were observed, but the CGRP receptor was predominantly expressed by second-order neurons of the TNC.…”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 89%

“…136 More detailed examination of tissues obtained from cynomolgus monkeys confirmed the presence of the CGRP receptor on dural vascular smooth muscle cell, neurons, and satellite glial cells of the TG and TNC neurons. 136 In that study, binding to both postsynaptic and presynaptic sites were observed, but the CGRP receptor was predominantly expressed by second-order neurons of the TNC. 136 …”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 89%

“…63,66 Other studies also found very little expression of CGRP receptors on neurons that also express the CGRP peptide. 136 The CGRP receptor is also highly expressed in the meningeal vasculature, which is innervated by primary afferent fibers from the TG that express CGRP. 63,66 Recent studies using antibodies that specifically recognize the CGRP-binding site, which was discovered by using a fusion protein of the extracellular domains of RAMP1 and CLR, showed binding to human TG neurons and human vascular smooth muscle cells of the meningeal vasculature.…”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 99%

“…185 In addition to its role in the somatosensory system, CGRP is also an extremely potent vasodilator, and vascular beds, including the mesenteric and the meningeal vasculatures, richly express CGRP receptors. 59,136 In the meninges, the middle meningeal and the cerebral arteries are innervated by primary afferent trigeminal fibers that express CGRP. 59,136 Evolving evidence of CGRP's role in the trigeminal system and the recent success of clinical trials with monoclonal antibodies directed at CGRP or its receptor, coupled with the clinical efficacy of CGRP receptor antagonists, have provided certain evidence that CGRP is a critical component for the pathogenesis of migraine.…”

Section: Introductionmentioning

confidence: 99%

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The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

PAIN

422

364

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Calcitonin gene–related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Aδ sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system. Calcitonin gene–related peptide was found to play important roles in cardiovascular, digestive, and sensory functions. Although the vasodilatory properties of CGRP are well documented, its somatosensory function regarding modulation of neuronal sensitization and of enhanced pain has received considerable attention recently. Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and the associated enhanced pain. Calcitonin gene–related peptide is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain. It is most likely that CGRP facilitates nociceptive transmission and contributes to the development and maintenance of a sensitized, hyperresponsive state not only of the primary afferent sensory neurons but also of the second-order pain transmission neurons within the central nervous system, thus contributing to central sensitization as well. The maintenance of a sensitized neuronal condition is believed to be an important factor underlying migraine. Recent successful clinical studies have shown that blocking the function of CGRP can alleviate migraine. However, the mechanisms through which CGRP may contribute to migraine are still not fully understood. We reviewed the role of CGRP in primary afferents, the dorsal root ganglion, and in the trigeminal system as well as its role in peripheral and central sensitization and its potential contribution to pain processing and to migraine.

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“…136 In that study, binding to both postsynaptic and presynaptic sites were observed, but the CGRP receptor was predominantly expressed by second-order neurons of the TNC. 136 …”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 79%

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 89%

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 89%

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

PAIN

422

364

View full text Add to dashboard Cite

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Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks

et al. 2018

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IMPORTANCE Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown. OBJECTIVE To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache. DESIGN, SETTING, AND PARTICIPANTSA randomized, double-blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse.INTERVENTIONS Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 μg/min of CGRP or placebo over 20 minutes on 2 study days.MAIN OUTCOMES AND MEASURES Difference in incidence of cluster headache-like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups. RESULTSOf 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide-induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99).CONCLUSIONS AND RELEVANCE Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs ma...

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A Pharmacokinetic Bioequivalence Study of Fremanezumab Administered Subcutaneously Using an Autoinjector and a Prefilled Syringe

Cherniakov

Cohen‐Barak

Tiver

et al. 2021

Clinical Pharm in Drug Dev

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Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following singledose administration,the mean concentration-time profiles for the 2 treatment groups (autoinjector,n = 106;and prefilled syringe, n = 110) were similar. The point estimates for the back-transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration-time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half-life was approximately 29 days. Treatment-related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment-emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy-to-use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.

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Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies

Cited by 60 publications

References 74 publications

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks

A Pharmacokinetic Bioequivalence Study of Fremanezumab Administered Subcutaneously Using an Autoinjector and a Prefilled Syringe

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