Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale

Cohen, Fred E.; Yuan, Hsiangkuo; Silberstein, Stephen D

doi:10.1007/s40259-022-00530-0

Cited by 21 publications

(8 citation statements)

References 139 publications

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“…The complex CGRP physiology accounts for the observed appropriate or detrimental effects of CGRP or CGRP receptor antagonist drugs in different clinical conditions [ 6 , 26 ]. To date, monoclonal antibodies targeting CGRP are available to treat migraines [ 43 ] and are safe in clinical practice in terms of COVID-19 infection susceptibility [ 44 , 45 ]. Moreover, it has been hypothesized that in COVID-19, a crosstalk between the lungs and the neuro–immune axis could take place, sustaining the development of a clinical trial aimed to investigate the effectiveness of vazegepant, an anti-CGRP molecule initially developed to treat migraines, in COVID-19 management [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients

Rizzi

Tonello

Morani

et al. 2022

Viruses

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SARS-CoV-2 is the etiological agent of COVID-19, an extremely heterogenous disease that can cause severe respiratory failure and critical illness. To date, reliable biomarkers allowing for early patient stratification according to disease severity are still lacking. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in lung pathophysiology and immune modulation and is poorly investigated in the COVID-19 context. In this observational, prospective cohort study, we investigated the correlation between CGRP and clinical disease evolution in hospitalized moderate to severe COVID-19 patients. Between January and May 2021 (Italian third pandemic wave), 135 consecutive SARS-CoV-2 patients were diagnosed as being eligible for the study. Plasma CGRP level evaluation and routine laboratory tests were performed on blood samples collected at baseline and after 7 days of hospitalization. At baseline, the majority our patients had a moderate to severe clinical presentation, and higher plasma CGRP levels predicted a higher risk of in-hospital negative evolution (odds-ratio OR 2.84 [IQR 1.07–7.51]) and were correlated with pulmonary intravascular coagulopathy (OR 2.92 [IQR 1.19–7.17]). Finally, plasma CGRP levels were also correlated with plasma IP10 levels. Our data support a possible crosstalk between the lung and the neuroimmune axis, highlighting a crucial role for plasma CGRP in sustaining COVID-19-related hyperinflammation.

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Section: Discussionmentioning

confidence: 99%

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients

Rizzi

Tonello

Morani

et al. 2022

Viruses

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“…CGRP-targeted monoclonal antibodies (mAbs) and gepants, as small-molecule antagonists, are two groups of therapeutic agents that have been elaborated to date to disrupt the function of CGRP. Currently, three gepants and four CGRP-targeted mAbs are approved by the United States (US) Food and Drug Administration (FDA) for treating migraine ( 153 ); three of the CGRP-targeted mAbs are against CGRP, and the other one is against the receptor of CGRP ( 154 ).…”

Section: Methodsmentioning

confidence: 99%

Immunologic aspects of migraine: A review of literature

et al. 2022

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Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.

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“…Since the small-diameter neurons are mainly C-fiber-related nociceptors [ 38 , 39 ], we conducted immunostaining CGRP and IB4 for labeling unmyelinated peptidergic or non-peptidergic sensory neurons, and NF200 for myelinated neurons [ 40 ]. Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of neuropathic pain [ 41 ], which is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization [ 42 ]. As expected in our study, Na v 1.7 expression is varied among three types of neurons after SNI, as an increment is shown in CGRP-labeled neurons, and such increment can be blunted by Narirutin administration.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel

Yang

Shan

Guo

et al. 2022

IJMS

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Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin’s antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs.

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Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale

Cited by 21 publications

References 139 publications

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients

Immunologic aspects of migraine: A review of literature

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel

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