Calcitonin gene-related peptide and its role in migraine pathophysiology

Arulmani, Udayasankar; MaassenVanDenBrink, Antoinette; Villalón, Carlos M.; Saxena, Pramod R.

doi:10.1016/j.ejphar.2004.07.035

Cited by 156 publications

(113 citation statements)

References 112 publications

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“…For example, CGRP seems to be a major cause of migraine through local vasodilatation of cerebral vessels by release from trigeminal sensory nerve terminals (Arulumani et al 2004). The AM gene is up-regulated in response to cardiac and renal failure or septic shock in proportion to the severity of the disease state (Eto et al 2003, Rademaker et al 2003.…”

Section: Discussionmentioning

confidence: 99%

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Takei¹,

Hashimoto

Inoue³

et al. 2008

Journal of Endocrinology

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Adrenomedullin 5 (AM5) is a new member of the calcitonin gene-related peptide (CGRP) family identified in teleost fish. Although its presence was suggested in the genome database of mammals, molecular identity and biological function of AM5 have not been examined yet. In this study, we cloned a cDNA encoding AM5 in the pig and examined its cardiovascular and renal effects. Putative mature AM5 was localized in the middle of prohormone and had potential signals for intermolecular ring formation and C-terminal amidation. The AM5 gene was expressed most abundantly in the spleen and thymus. Several AM5 genes were newly identified in the database of mammals, which revealed that the AM5 gene exists in primates, carnivores, and undulates but could not be identified in rodents. In primates, nucleotide deletion occurred in the mature AM5 sequence in anthropoids (human and chimp) during transition from the rhesus monkey. Synthetic mature AM5 injected intravenously into rats induced dose-dependent decreases in arterial pressure at 0 . 1-1 nmol/kg without apparent changes in heart rate. The decrease was maximal in 1 min and AM5 was approximately half as potent as AM. AM5 did not cause significant changes in urine flow and urine Na C concentration at any dose. In contrast to the peripheral vasodepressor action, AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate at 0 . 1-1 nmol. The increase reached maximum more quickly after AM5 (5 min) than AM (15-20 min). AM5 added to the culture cells expressing calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of the receptor activitymodifying proteins (RAMPs), the combination of which forms major receptors for the CGRP family, did not induce appreciable increases in cAMP production in any combination, although AM increased it at 10 K10 -10 K9 M when added to the CLR and RAMP2/3 combination. These data indicate that AM5 seems to act on as yet unknown receptor(s) for AM5, other than CLR/CTRCRAMP, to exert central and peripheral cardiovascular actions in mammals.

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Section: Discussionmentioning

confidence: 99%

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Takei¹,

Hashimoto

Inoue³

et al. 2008

Journal of Endocrinology

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“…On the basis of pharmacological criteria, it is known that CGRP may act mainly on CGRP 1 and CGRP 2 receptors (Arulmani et al 2004), with h-αCGRP 8-37 being a 10-fold more potent antagonist at CGRP 1 receptors than at CGRP 2 receptors (Quirion et al 1992 Gupta et al 2006a;Jansen-Olesen et al 2003;Oliver et al 2002). The results from our laboratory also advocate the presence of CGRP 1 receptors in human meningeal (Gupta et al 2006a) and coronary (Gupta et al 2006b) arteries, while in human distal coronary artery, there seems to be an additional population of CGRP receptors not complying with the current classification of CGRP 1 or CGRP 2 receptors (Gupta et al 2006b).…”

Section: Cgrp Receptorsmentioning

confidence: 99%

“…Although the brain is insensitive to pain, nociceptive stimuli can be generated by large cranial and proximal intracranial blood vessels, as well as by the dura mater. Evidence for peripheral trigeminal activation in migraine is provided by the release of calcitonin gene-related peptide (CGRP; Arulmani et al 2004;Goadsby and Lance 1990) even though the mechanism of generation of pain is not clear. Studies in animals have suggested that the pain may be caused by a sterile neurogenic inflammatory process in the dura mater (Moskowitz and Cutrer 1993), but this mechanism has not been clearly established to correlate in humans (May et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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“…Elevated levels of CGRP, but not of other neuropeptides, were found in the external jugular vein during the headache phase of migraine and normalized in parallel with headache improvement [22,23]. Furthermore, infusion of human CGRP was found to trigger a migraine attack in susceptible individuals, while normalization of CGRP levels were obtained after migraine treatment with triptans [24][25][26].…”

Section: Pathophysiologymentioning

confidence: 98%

Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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Migraine is a highly prevalent headache disease that typically affects patients during their most productive years. Despite significant progress in understanding the underlying pathophysiology of this disorder, its treatment so far continues to depend on drugs that, in their majority, were not specifically designed for this purpose. The neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack. It is not surprising that drugs designed to specifically block its action are gaining remarkable attention from researchers in the field with, at least so far, a safe risk profile. In this article, we highlight the evolution from older traditional treatments to the innovative CGRP target drugs that are revolutionizing the way to approach this debilitating neurological disease. We provide a brief introduction on pathophysiology of migraine and details on the characteristic, function, and localization of CGRP to then focus on CGRP receptor antagonists (CGRP-RAs) and CGRP monoclonal antibodies (CGRP mAbs). Key PointsThe neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack.Targeting CGRP as a specific therapeutic tool for migraine may offer similar or even better efficacy than currently available treatments without the vasoconstrictive risk factors.Further studies are necessary to determine the exact role of CGRP receptor antagonists and CGRP monoclonal antibodies in migraine with aura, allodynia, and photophobia.

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Calcitonin gene-related peptide and its role in migraine pathophysiology

Cited by 156 publications

References 112 publications

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Current and prospective pharmacological targets in relation to antimigraine action

Targeting CGRP: A New Era for Migraine Treatment

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