Calcitonin Gene-related Peptide In Migraine Research Articles

CGRP: from neuropeptide to the therapeutic target (background and pathophysiology)

Calcitonin gene-related peptide (CGRP) plays a pivotal role in migraine pathophysiology. The importance of CGRP in migraine became evident from numerous clinical studies investigating CGRP levels both interictally and ictally and reports on the efficacy of CGRP-based migraine therapies. In this paper, the above mentioned studies will be presented and the reader will be introduced to the development of CGRP-based medication. Finally, current study results on CGRP receptor antagonists, the so-called gepants, will be presented.

The evolving landscape and research trend of calcitonin gene-related peptide in migraine: A bibliometric analysis and visualization.

Migraine is a global public health concern, affecting both social and individual well-being. Calcitonin gene-related peptide (CGRP), a crucial neuropeptide, holds important research value in understanding migraine pathogenesis. CGRP receptor antagonists and monoclonal antibodies that target CGRP or its receptors have shown efficacy in reducing migraine frequency and severity, presenting a promising therapeutic approach. This study aimed to conduct a comprehensive bibliometric analysis to analyze the current state, research trends, and future directions of CGRP in migraine. Bibliometric tools including CiteSpace, VOSviewer, etc., were utilized to extract and summarize publications related to CGRP in migraine from the Web of Science Core Collection Database (WOSCC) between 2004 and 2023, as of December 31, 2023. The analysis focused on trends in annual publications, leading countries/regions and institutions, prominent journals and references, influential authors, and high-frequency keywords in the field. A total of 1,821 articles and reviews involving 5,180 authors from 1,315 organizations across 64 countries were included in the study. These publications were distributed across 362 journals and accumulated 56,999 citations by December 31, 2023. An increasing trend was observed in annual publications on CGRP in migraine. The United States emerged as the leading nation in both publications and citations, with academic Peter Goadsby contributing the highest number of publications. The University of Copenhagen stood out as the institution with the most publications, and Cephalalgia emerged as the most influential journal. The most cited paper identified was "Calcitonin gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine" by Jes Olesen, published in the New Engl Med. Keyword frequency analysis revealed prevalent terms such as "migraine," "CGRP," and "episodic migraine," along with emerging topics represented by keywords including "trial," "monoclonal antibodies," "preventive treatment," and "safety." CGRP is pivotal in migraine pathogenesis, and there is a robust research foundation exploring its role. The US leads in research output on CGRP in migraine. Investigating the mechanism of CGRP and its receptor in migraine remains a key area of interest, particularly focusing on signaling pathways. Future research should target identifying critical therapeutic targets in CGRP antagonist pathways for migraine treatment.

CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in sensory neurons as well as in other cell types, such as motor neurons and neuroendocrine cells. CGRP acts via at least two G protein-coupled receptors that form unusual complexes with receptor activity-modifying proteins. These are the CGRP receptor and the AMY1 receptor; in rodents, additional receptors come into play. Although CGRP is known to produce many effects, the precise molecular identity of the receptor(s) that mediates CGRP effects is seldom clear. Despite the many enigmas still in CGRP biology, therapeutics that target the CGRP axis to treat or prevent migraine are a bench-to-bedside success story. This review provides a contextual background on the regulation and sites of CGRP expression and CGRP receptor pharmacology. The physiological actions of CGRP in the nervous system are discussed, along with updates on CGRP actions in the cardiovascular, pulmonary, gastrointestinal, immune, hematopoietic, and reproductive systems and metabolic effects of CGRP in muscle and adipose tissues. We cover how CGRP in these systems is associated with disease states, most notably migraine. In this context, we discuss how CGRP actions in both the peripheral and central nervous systems provide a basis for therapeutic targeting of CGRP in migraine. Finally, we highlight potentially fertile ground for the development of additional therapeutics and combinatorial strategies that could be designed to modulate CGRP signaling for migraine and other diseases.

Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine.

The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, CALCA, is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the CALCA gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the CALCA primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.

Кальцитонін-ген-зв’язаний пептид при мігрені: патогенетичний фактор та терапевтична мішень (огляд)

Кальцитонін-ген-зв’язаний пептид відіграє ключову роль у патофізіології мігрені. Під час нападу мігрені кальцитонін-ген-зв’язаний пептид виділяється з нейронів трійчастого ганглія, що призводить до вивільнення прозапальних медіаторів і розширення краніальних судин. Вазодилатація і нейрогенне запалення сприяють активації сенсорних волокон трійчастого нерва, подальшому вивільненню вазоактивних речовин, у тому числі кальцитонін-гензв’язаного пептиду, і модуляції передачі больових імпульсів у головний мозок. Сьогодні кальцитонін-ген-зв’язаний пептид є мішенню, що найбільш активно вивчається, для дослідження антимігренозних препаратів. У даній статті висвітлено результати недавніх досліджень препаратів — антагоністів рецепторів кальцитонін-ген-зв’язаного пептиду, що вивчалися для купірування нападів епізодичної мігрені, а також ряду моноклональних антитіл для превентивного лікування. У рандомізованих плацебо-контрольованих дослідженнях показано, що людські моноклональні антитіла проти кальцитонін-ген-зв’язаного пептиду і його рецепторів є ефективними і безпечними для профілактики епізодичної і хронічної мігрені.

Galcanezumab effectiveness on comorbid cluster headache and chronic migraine: a prospective case series.

Cluster headache (CH) and migraine are recurrent painful primary cephalalgies, typically with different clinical appearance and some shared features, such as unilateral pain, common triggers and response to triptans and/or monoclonal antibodies against the calcitonin gene-related peptide (CGRP) pathway. Common pathophysiological mechanisms are proposed in CH and migraine, including the role of the trigeminal-vascular system with its most representative neuropeptide, CGRP. Very few case series have been conducted so far investigating anti-CGRP treatments in patients with comorbid CH and migraine, and no cases have been reported which assess both CH and chronic migraine outcomes. We describe 4 patients with both chronic migraine and cluster headache, with or without failure to preventive medications. Galcanezumab (240mg loading dose, followed by 120mg monthly) was used for at least a 3-month treatment, demonstrating improvement in both migraine and CH outcomes (i.e. migraine days, CH attacks, Headache Impact Test -6 item score, acute medications use), achieving sustained clinical benefit. No adverse events were reported. Taking into account the role of CGRP in migraine and CH pathophysiology, a usually well-tolerated treatment with CGRP blockade could be a rationale-based option to treat patients with coexisting chronic migraine and cluster headache. Additional studies are needed to assess the role of anti-CGRP drugs in episodic and chronic CH treatment, as well as to establish correct timing and patient prerequisites to begin therapy.

Hypervigilance, Allostatic Load, and Migraine Prevention: Antibodies to CGRP or Receptor.

Migraine involves brain hypersensitivity with episodic dysfunction triggered by behavioral or physiological stressors. During an acute migraine attack the trigeminal nerve is activated (peripheral sensitization). This leads to central sensitization with activation of the central pathways including the trigeminal nucleus caudalis, the trigemino-thalamic tract, and the thalamus. In episodic migraine the sensitization process ends with the individual act, but with chronic migraine central sensitization may continue interictally. Increased allostatic load, the consequence of chronic, repeated exposure to stressors, leads to central sensitization, lowering the threshold for future neuronal activation (hypervigilance). Ostensibly innocuous stressors are then sufficient to trigger an attack. Medications that reduce sensitization may help patients who are hypervigilant and help to balance allostatic load. Acute treatments and drugs for migraine prevention have traditionally been used to reduce attack duration and frequency. However, since many patients do not fully respond, an unmet treatment need remains. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in nociception and in the sensitization of peripheral and central neurons of the trigeminovascular system, which is implicated in migraine pathophysiology. Elevated CGRP levels are associated with dysregulated signaling in the trigeminovascular system, leading to maladaptive responses to behavioral or physiological stressors. CGRP may, therefore, play a key role in the underlying pathophysiology of migraine. Increased understanding of the role of CGRP in migraine led to the development of small-molecule antagonists (gepants) and monoclonal antibodies (mAbs) that target either CGRP or the receptor (CGRP-R) to restore homeostasis, reducing the frequency, duration, and severity of attacks. In clinical trials, US Food and Drug Administration-approved anti-CGRP-R/CGRP mAbs were well tolerated and effective as preventive migraine treatments. Here, we explore the role of CGRP in migraine pathophysiology and the use of gepants or mAbs to suppress CGRP-R signaling via inhibition of the CGRP ligand or receptor.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00250-7.

Reducing Episodic Cluster Headaches: Focus on Galcanezumab.

The involvement of calcitonin gene-related peptide in migraine and cluster headache has led to the recent development of new therapies. Galcanezumab, a novel monoclonal antibody targeting the calcitonin gene-related peptide, is approved for the migraine prevention and has recently been tested for the prevention of cluster headache. Two clinical trials have been conducted to investigate the efficacy and safety of galcanezumab in episodic cluster headache and chronic cluster headache. While efficacy endpoints were not met in the chronic subtype, galcanezumab reduced the weekly frequency of attacks in patients with episodic cluster headaches. In both studies, the antibody was well tolerated. This review summarizes and critically reviews the available data regarding the rationale behind targeting the calcitonin gene-related peptide with galcanezumab for the prevention of cluster headache.

Calcitonin Gene-Related Peptide Targeting Therapies for Migraine: A New Era for Migraine Treatment

Development of medications targeting the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor has ushered in the new era for the treatment of migraine. Some of these drugs are approved by the USA Food and Drug Administration and European Medicines Agency since 2018, and others are in the process of approval. Since the CGRP-related therapies act directly on the migraine pathophysiology, they have advantages over conventional treatments not only in effect but also in terms of adverse effects. CGRP receptor antagonist have an effect on both acute and preventive treatment of migraine, while monoclonal antibodies for CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) or receptor (erenumab) reduce migraine frequency and related disability. Galcanezumab was approved by the Ministry of Food and Drug Safety in Korea in September 2019. As of December 2019, it is available for use in adult patients with migraine. We describe the pathophysiology of CGRP in migraine, summarize the results of recent CGRP antagonism related clinical trials, and provide opinions about the use of CGRP-related therapies in clinical practice.

Clinical Study of Chronic Heredofamilial Migraine with Aura

Sixteen patients ranging from 19 to 68 years-old were studied with Chronic Heredofamilial Migraine with Aura. The following symptoms were associated to chronic heredofamilial migraine: dizziness, vertigo, syncope, redness eye, photophobia, blurred vision and reduced and loss of vision, scintillant scotomas, dizziness, ears noise, temporospatial disorientation, memory disorders, effort dyspnea, asthenia, son phobia, nausea, vomits, and social, labor and home stress. The followings symptoms were interpreted as migraine auras: Blurred vision and reduced and loss of vision, scintillant scotomas, dizziness, ears noise. The following comorbidities were found: syncope, bradycardia, mitral prolapse and tachycardia, effort dyspnea, asthenia, seizures, environment, labor and home stress, sleep disorders or insomnia and constipation. The followings aspects were discussed: migraine and prodroms, migraine and vascular diseases, migrainous vertigo and dizziness, symptoms related to the visual system in migraine, migraine and sleep disorders, hemiplegic migraine, neural correlates of migraine, histamine and migraine, the calcitonin gene-related peptide in migraine and its role in migraine physiopathology, and migraine genetic

Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models.

Migraine is the second leading cause for disability worldwide and the most common neurological disorder. It is also three times more common in women; reasons for this sex difference are not known. Using preclinical behavioral models of migraine, we show that application of calcitonin gene-related peptide (CGRP) to the rat dura mater produces cutaneous periorbital hypersensitivity. Surprisingly, this response was observed only in females; dural CGRP at doses from 1 pg to 3.8 μg produce no responses in males. In females, dural CGRP causes priming to a pH 7.0 solution after animals recover from the initial CGRP-induced allodynia. Dural application of interleukin-6 causes acute responses in males and females but only causes priming to subthreshold dural CGRP (0.1 pg) in females. Intracisternal application of BDNF also causes similar acute hypersensitivity responses in males and females but only priming to subthreshold dural CGRP (0.1 pg) in females. Females were additionally primed to a subthreshold dose of the NO-donor sodium nitroprusside (0.1 mg/kg) following dural CGRP. Finally, the sexually dimorphic responses to dural CGRP were not specific to rats as similar female-specific hypersensitivity responses were seen in mice, where increased grimace responses were also observed. These data are the first to demonstrate that CGRP-induced headache-like behavioral responses at doses up to 3.8 μg are female-specific both acutely and following central and peripheral priming. These data further implicate dural CGRP signaling in the pathophysiology of migraine and propose a model where dural CGRP-based mechanisms contribute to the sexual disparity of this female-biased disorder.SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) has long been implicated in the pathophysiology of migraine, and CGRP-based therapeutics are efficacious for the treatment of migraine in humans. However, the location of action for CGRP in migraine remains unclear. We show here that application of CGRP to the cranial meninges causes behavioral responses consistent with headache in preclinical rodent models. Surprisingly, however, these responses are only observed in females. Acute responses to meningeal CGRP are female-specific and sensitization to CGRP after two distinct stimuli are also female-specific. These data implicate the dura mater as a primary location of action for CGRP in migraine and suggest that female-specific mechanisms downstream of CGRP receptor activation contribute to the higher prevalence of migraine in women.

Role of CGRP in Migraine.

Migraine is a common neurological disorder that afflicts up to 15% of the adult population in most countries, with predominance in females. It is characterized by episodic, often disabling headache, photophobia and phonophobia, autonomic symptoms (nausea and vomiting), and in a subgroup an aura in the beginning of the attack. Although still debated, many researchers consider migraine to be a disorder in which CNS dysfunction plays a pivotal role while various parts of the trigeminal system are necessary for the expression of associated symptoms.Treatment of migraine has in recent years seen the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are now approved for use in frequent episodic and in chronic migraine. CGRP-related therapies offer considerable improvements over existing drugs, as they are the first to be designed specifically to act on the trigeminal pain system: they are more specific and have little or no adverse effects. Small molecule CGRP receptor antagonists, gepants, are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (Eptinezumab, Fremanezumab, and Galcanezumab) or the CGRP receptor (Erenumab) effectively prevent migraine attacks. The neurobiology of CGRP signaling is briefly summarized together with key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatments.

Cortical spreading depression as a site of origin for migraine: Role of CGRP.

Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

CGRP Monoclonal Antibodies for Migraine: Rationale and Progress.

Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood-brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs.

Gender aspects of CGRP in migraine.

BackgroundMigraine is two to three times more prevalent in women than in men, but the mechanisms involved in this gender disparity are still poorly understood. In this respect, calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology and, more recently, the functional interactions between ovarian steroid hormones, CGRP and the trigeminovascular system have been recognized and studied in more detail.AimsTo provide an overview of CGRP studies that have addressed gender differences utilizing animal and human migraine preclinical research models to highlight how the female trigeminovascular system responds differently in the presence of varying ovarian steroid hormones.ConclusionsGender differences are evident in migraine. Several studies indicate that fluctuations of ovarian steroid hormone (mainly estrogen) levels modulate CGRP in the trigeminovascular system during different reproductive milestones. Such interactions need to be considered when conducting future animal and human experiments, since these differences may contribute to the development of gender-specific therapies.

The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine.

The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials. However, there is still much to learn about the role of CGRP and CGRP receptors in headache pathophysiology, the critical anatomical sites, peripheral or central, of anti-CGRP agents, and the potential involvement of CGRP-related peptides and receptors. This review provides a brief history of the discovery of the role of CGRP in migraine and highlights current progress in understanding the complexity of the trigeminovascular pathway and its peptide transmitters.

Amylin

Amylin is a 37 amino acid peptide hormone that is closely related to calcitonin gene-related peptide (CGRP). Amylin and CGRP share a receptor and are reported to have several similar biological actions. Given the important role of CGRP in migraine and intense efforts to develop drugs against this target, it is important to consider potential areas of overlap between the amylin and CGRP systems. This short review provides a brief introduction to amylin biology, the use of an amylin analog to treat diabetes, and consideration of whether amylin could have any role in headache disorders. Finally, this review informs readers about the AMY1 (amylin subtype 1) receptor, which is a dual receptor for amylin and CGRP and potentially plays a role in the bioactivity of both of these peptides.

Calcitonin gene-related peptide and migraine.

Migraine is a common, complex disorder of the brain with significant morbidity. As the pathophysiology of the disorder has become better appreciated, the role of neuropeptides has been explored. Calcitonin gene-related peptide (CGRP) has emerged as a promising therapeutic target. CGRP is widely distributed in the nervous system, particularly at anatomical areas thought to be involved with migraine, including the trigeminovascular nociceptive system. In studies, CGRP has been shown to be released during severe migraine attacks, and effective triptan treatment of an attack normalizes these levels. CGRP administration triggers migraine in patients and CGRP receptor antagonists can abort migraine. Moreover, recent data demonstrate that CGRP mechanism blockade either by small molecule receptor antagonists or by monoclonal antibodies can have a preventive effect in migraine. This article highlights the evidence behind the role of CGRP in migraine and the state of CGRP-based mechanism treatment development. We present a summary of the evidence base behind CGRP in migraine pathophysiology and the novel CGRP mechanism drugs and their potential future contribution to migraine management in our clinical practice.

CGRP as a new target in prevention and treatment of migraine

CGRP as a new target in prevention and treatment of migraine

Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine.

Calcitonin gene-related peptide (CGRP) is a potent neuromodulator and vasodilator. It has been implicated in the pathogenesis of migraine by a number of lines of evidence, although its precise role has yet to be fully defined. Compelling evidence for the importance of CGRP in migraine has been provided by clinical trials with multiple small molecule CGRP receptor antagonists. These clinical studies have shown that blockade of the CGRP receptor can produce antimigraine efficacy comparable to that of the gold standard triptan class of drugs with an incidence of adverse events that appears to be relatively low. The present review describes the discovery and development of these new antimigraine agents and highlights the challenges of identifying orally acting drugs that target a family B G-protein-coupled receptor.