CGRP and CGRP-receptor as targets of migraine therapy: Brain Prize-2021

2021 ◽  
Vol 20 ◽  
Author(s):  
János Tajti ◽  
Délia Szok ◽  
Aliz Nyári ◽  
László Vécsei
Keyword(s):  
Meta Analysis ◽  
Primary Headache ◽  
Calcitonin Gene Related Peptide ◽  
Trigeminovascular System ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
New Treatments ◽  
Preclinical And Clinical Studies ◽  
The Brain ◽  
Therapeutic Perspective

Background : Migraine is a highly prevalent primary headache with an unclear pathomechanism. During the last 40 years numerous hypotheses have arisen, among them the theory of the trigeminovascular system is the primary one. It serves as a skeleton in successful preclinical studies and in the development of effective therapeutic options for migraine headache. Objective : The Brain Prize (awarded annually by the Lundbeck Foundation) is the most prestigious tribute in neuroscience. The winners in 2021 were Lars Edvinsson, Peter Goadsby, Michael Moskowitz and Jes Olesen. They are the fathers of the migraine pathomechanism which led to revolutionary new treatments. This review summarizes their landmark findings. Methods : Data related to this topic were reviewed from PubMed records published between 1979 and May 2021. Searches were based on preclinical and clinical studies in the covered field. The findings were listed in chronological order. From a therapeutic perspective, only randomized controlled trials and meta-analysis were discussed. Results: The calcitonin gene-related peptide-related pathogenesis of migraine is based on the activation of the trigeminovascular system. The therapeutic triad for migraine is triptans, gepants and calcitonin gene-related peptide-targeted monoclonal antibodies. Conclusion: In the past 40 years, the systematic work of leading headache scientists has resulted in robust theoretical and therapeutic knowledge in the preclinical and clinical study of migraine.

scholarly journals Role of Calcitonin Gene Related Peptide (CGRP) in Migraine

2017 ◽  
Vol 33 (1) ◽  
pp. 39-43
Author(s):  
Md Ashraf Ali ◽  
Habibur Rahaman
Keyword(s):  
Family Relationships ◽  
Preventive Treatment ◽  
Primary Headache ◽  
Calcitonin Gene Related Peptide ◽  
Childhood And Adolescence ◽  
Protein Extravasation ◽  
Related Peptide ◽  
Plasma Protein Extravasation ◽  
Calcitonin Gene ◽  
Potent Vasodilator

Migraine is the second most primary headache. The prevalence of Migraine is 12% in the general population, including 18% in women and 6% in men. Migraine can start in childhood and adolescence and continue throughout lifespan. It is most prevalent among people in their 30s and 40s. Migraine is a debilitating hemicranial headache that is pulsating, aggravated by movement, nausea, vomiting and having sensitivity to light and sound, with or without aura. It can affect all aspects of life as work and school, parenting and family relationships and personal and leisure time. There are some theory regarding pathogenesis of migraine which includes cortical spreading depression, cortical spreading oligemia, activation of trigeminocervical complex leading to neuroinflammation & release of vasodialating neuropeptides which include calcitonin gene related peptide (CGRP), substance P, vasoactive intestinal polypeptide (VIP), nitric oxide (NO), and pituitary adenylate cyclase activating peptide (PACAP) & genetic factor. CGRP is a potent vasodilator and causes perivascular plasma protein extravasation and nociceptive pain. Newer medications target CGRP both for acute and preventive treatment of migraine. Bangladesh Journal of Neuroscience 2017; Vol.  33 (1): 39-43

scholarly journals Effect of Calcitonin Gene-Related Peptide Receptor Antagonists on Migraine Treatment: A Meta-Analysis

2021 ◽  
Author(s):  
Jiyoung Kim ◽  
Kyoungjune Pak ◽  
Gha-Hyun Lee ◽  
Jae Wook Cho ◽  
Hyun-Woo kim
Keyword(s):  
Meta Analysis ◽  
Calcitonin Gene Related Peptide ◽  
Migraine Treatment ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Acute Migraine Treatment

Abstract Background: The pathophysiology of migraine has been researched incessantly, and it has been suggested that calcitonin gene-related peptide (CGRP) is associated with migraine attacks. CGRP receptor blockers are attracting attention for migraine prevention and treatment of acute episodes, and CGRP receptor antagonists have been shown to be effective in treating acute migraine headaches. This meta-analysis aimed to assess the effect of available CGRP receptor antagonists, focusing on their therapeutic doses for acute migraine treatment.Methods: We performed a systematic search of MEDLINE (from inception to March 2021) and EMBASE (from inception to March 2021) for English publications using the keywords “migraine” and “Calcitonin gene-related peptide,” limited to human studies.Results: Five studies that focused on examining the effects of CGRP receptor antagonists on acute migraine treatment met the eligibility criteria for this meta-analysis. The pooled analysis demonstrated that the CGRP receptor antagonist improved freedom from pain (OR=2.066, 95% confidence interval [CI] 1.766–2.418, I2=0%), absence of bothersome symptoms (OR=1.606, 95% CI=1.408–1.830, I2=0%), pain relief (OR=1.791, 95% CI=1.598–2.008, I2=0%), and freedom from nausea (OR=1.361, 95% CI=1.196–1.548, I2=0%), significantly more than the placebo. Conclusions: CGRP receptor antagonists are effective for acute migraine treatment and are expected to be used clinically as emerging therapeutic agents.

Safety and tolerability of calcitonin-gene-related peptide binding monoclonal antibodies for the prevention of episodic migraine – a meta-analysis of randomized controlled trials

Cephalalgia ◽  
2019 ◽  
Vol 39 (9) ◽  
pp. 1164-1179 ◽  
Author(s):  
Da Xu ◽  
Deng Chen ◽  
Li-na Zhu ◽  
Ge Tan ◽  
Hai-jiao Wang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Adverse Events ◽  
Injection Site ◽  
Meta Analysis ◽  
Peptide Binding ◽  
Episodic Migraine ◽  
Calcitonin Gene Related Peptide ◽  
Serious Adverse Events ◽  
Related Peptide ◽  
Calcitonin Gene

Aim To systematically evaluate the safety and tolerability of calcitonin-gene-related peptide binding monoclonal antibodies from the results of randomized controlled trials. Methods Online databases were searched on calcitonin-gene-related peptide binding monoclonal antibodies for the prevention of episodic migraine. Overall withdrawal, withdrawal due to adverse events, adverse events, serious adverse events and specific adverse events were extracted from the included studies. A meta-analysis was performed with Revman 5.3.0 software. Results Ten studies that investigated four drugs (galcanezumab, erenumab, fremanezumab and eptinezumab) with 5817 participants were included in this study. Serious adverse events, overall withdrawals, withdrawal due to adverse events and any adverse events were not significantly associated with monoclonal antibody treatment. Injection site pain and erythema were significantly higher in the calcitonin-gene-related peptide binding monoclonal antibodies treatment group than in the placebo group. The rates of serious adverse events were significantly higher in the galcanezumab 120 mg group. Injection site erythema was associated with galcanezumab 120 mg and 240 mg. Injection site pain and nasopharyngitis were associated with galcanezumab 150 mg and 5 mg, respectively. Overall adverse events were significantly higher with erenumab 70 mg and 140 mg. Treatment-related adverse events were significantly higher with fremanezumab 225 mg/month and 675 mg/quarter. Conclusions This study provides data on the safety and tolerability profiles of calcitonin-gene-related peptide binding monoclonal antibodies and confirms their potential use as preventive treatments for episodic migraine. In addition to the acceptable withdrawal rates, serious adverse events were rare, and the severity of most adverse events was mild to moderate. Injection site reaction may be the major adverse event associated with galcanezumab.

scholarly journals Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system

Pain ◽  
2020 ◽  
Vol 161 (5) ◽  
pp. 1092-1099 ◽  
Author(s):  
Alejandro Labastida-Ramírez ◽  
Eloísa Rubio-Beltrán ◽  
Kristian A. Haanes ◽  
Kayi Y. Chan ◽  
Ingrid M. Garrelds ◽  
...  
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Trigeminovascular System ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Peptide Release

Oxytocin as a regulatory neuropeptide in the trigeminovascular system: Localization, expression and function of oxytocin and oxytocin receptors

Cephalalgia ◽  
2020 ◽  
Vol 40 (12) ◽  
pp. 1283-1295
Author(s):  
Karin Warfvinge ◽  
Diana N Krause ◽  
Aida Maddahi ◽  
Anne-Sofie Grell ◽  
Jacob CA Edvinsson ◽  
...  
Keyword(s):  
Dura Mater ◽  
Calcitonin Gene Related Peptide ◽  
Trigeminal Ganglia ◽  
Trigeminal Nucleus ◽  
Trigeminovascular System ◽  
Related Peptide ◽  
Oxytocin Receptors ◽  
Calcitonin Gene ◽  
And Function ◽  
Cranial Arteries

Background Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents. Methods The methods include immunohistochemistry, messenger RNA measurements, quantitative PCR, release of calcitonin gene-related peptide and myography of arterial segments. Results Oxytocin receptor mRNA was expressed in rat trigeminal ganglia and the receptor protein was localized in numerous small to medium-sized neurons and thick axons characteristic of A∂ sensory fibers. Double immunohistochemistry revealed only a small number of neurons expressing both oxytocin receptors and calcitonin gene-related peptide. In contrast, double immunostaining showed expression of the calcitonin gene-related peptide receptor component receptor activity-modifying protein 1 and oxytocin receptors in 23% of the small cells and in 47% of the medium-sized cells. Oxytocin immunofluorescence was observed only in trigeminal ganglia satellite glial cells. Oxytocin mRNA was below detection limit in the trigeminal ganglia. The trigeminal nucleus caudalis expressed mRNA for both oxytocin and its receptor. K+-evoked calcitonin gene-related peptide release from either isolated trigeminal ganglia or dura mater and it was not significantly affected by oxytocin (10 µM). Oxytocin directly constricted cranial arteries ex vivo (pEC50 ∼ 7); however, these effects were inhibited by the vasopressin V1A antagonist SR49059. Conclusion Oxytocin receptors are extensively expressed throughout the rat trigeminovascular system and in particular in trigeminal ganglia A∂ neurons and fibers, but no functional oxytocin receptors were demonstrated in the dura and cranial arteries. Thus, circulating oxytocin may act on oxytocin receptors in the trigeminal ganglia to affect nociception transmission. These effects may help explain hormonal influences in migraine and offer a novel way for treatment.

scholarly journals Efficacy of Calcitonin Gene-Related Peptide Antagonists in the Treatment of Acute Migraine: A Systematic Review and Meta-analysis

2019 ◽  
Vol 53 (1) ◽  
Author(s):  
Kristina M. Canlas ◽  
Regina A. Macalintal-Canlas ◽  
Fumihiko Sakai
Keyword(s):  
Pain Relief ◽  
Meta Analysis ◽  
Calcitonin Gene Related Peptide ◽  
Acute Migraine ◽  
Post Dose ◽  
Related Peptide ◽  
Randomized Controlled ◽  
Superior Efficacy ◽  
Calcitonin Gene ◽  
The Difference

Objective. This study determined the efficacy of calcitonin gene-related peptide (CGRP) antagonists in the treatment of acute migraine. Methods. Seven randomized, controlled trials were included. Outcome measures used were pain freedom and pain relief two hours after treatment. Results. The difference in pain freedom 2 hours post-dose significantly favored gepants 140/150 mg (OR=2.39, 95% CI=1.93-2.96, P<0.00001) and 280/300 mg (OR=2.94, 95% CI=2.44-3.35, P<0.00001) over placebo, while the difference in pain freedom 2 hours post- dose did not significantly favor triptans over gepants 140/150 mg and vice versa (OR=0.62, 95% CI=0.32-1.21, P=0.16) and over gepants 280/300 mg (OR=0.86, 95% CI=0.64-1.15, P=0.34). The difference in pain relief 2 hours post-dose significantly favored gepants 140/150 mg (OR=2.49, 95% CI=2.13-2.91, P<0.00001) and 280/300 mg (OR=2.78, 95% CI=2.41-3.21, P<0.00001) over placebo. The difference in pain relief 2 hours post-dose significantly favored triptans over gepants 140/150 mg (OR=0.73, 95% CI=0.56-0.96, P=0.03), but not over gepants 280/300 mg and vice versa (OR=0.98, 95% CI=0.76-1.27, P=0.89). Conclusion. With regard to pain freedom and pain relief two hours post-dose, CGRP antagonists are more efficacious than placebo in the treatment of acute migraine but there is insufficient evidence to demonstrate superior efficacy of CGRP antagonists over triptans.

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