Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

Abstract

Calcitonin gene-related peptide (CGRP) is a ubiquitous neuropeptide found at the very centers of the migraine process, both centrally and peripherally. It has been under careful study for approximately 25 years. Several CGRP-receptor antagonists are being evaluated for acute treatment of episodic migraine. Three monoclonal antibodies are being studied for prevention of episodic migraine, and 1 monoclonal antibody is being studied for prevention of chronic migraine. In this review, we discuss the role of CGRP in normal physiology and the consequences of CGRP inhibition for human homeostasis. We then review the current state of development for CGRP-receptor antagonists and CGRP monoclonal antibodies. We close by speculating on the potential clinical role of CGRP antagonism in the acute and preventive treatment of episodic and chronic migraine.Key words: calcitonin gene-related peptide, antibodies, migraine, chronic migraine (Headache 2013;53:1230-1244 Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide that is derived from the gene encoding calcitonin by alternative splicing of mRNA and proteolytic processing of its precursor. 1,2Despite their common origin, calcitonin and CGRP are involved in totally different physiological processes in humans. While calcitonin is mainly related to calcium homeostasis and bone remodeling, CGRP is involved in vasodilation and sensory transmission.CGRP is found in literally every organ system in the body, 3 occurring in 2 isoforms, a-and b-CGRP. 4,5a-CGRP is the predominant form in the peripheral nervous system, while the b-isoform is mainly present in the enteric nervous system. 6 CGRP is highly conserved across species, 7 suggesting that the neuropeptide is of importance in functions that were established relatively early in mammalian evolution.Immunohistochemistry demonstrated that CGRP is mainly produced in the cell bodies of both ventral and dorsal root neurons.8 Radioimmunology further demonstrated that this molecule is especially common in the trigeminal system, where up to 50% of the neurons produce it.9 Indeed, the potential role of CGRP in migraine pathophysiology was suggested more than 20 years ago, 10,11 and since then, our knowledge of the peptide and its role in the pathophysiology of migraine has increased substantially and has

Migraine and neuropeptides

“…Recent data point to the pivotal role of the neuron-glia interaction in the TRIG (Thalakoti et al, 2007;Vollbracht and Rapoport, 2013). The release of CGRP during the neuronal activation of the TRIG stimulates the SGCs, which release proinflammatory cytokines, thereby further modulating the neuronal response (Bigal et al, 2013;Thalakoti et al, 2007;Vecsei et al, 2015;Vollbracht and Rapoport, 2013). This observation permits a new approach to an understanding of the intraganglionic signalling process.…”

“…CGRP is a very potent endogenous vasodilatory neuropeptide in the cerebral vasculature (Edvinsson and Uddman, 2005;Edvinsson et al, 2012). During activation of the TS, CGRP gives rise to neurogenic inflammation (vasodilatation and plasma protein extravasation) in the meningeal vasculature and to mast cell degranulation; this process leads to peripheral sensitization (Bigal et al, 2013;Lennerz et al, 2008;Messlinger et al, 2011;Raddant and Russo, 2011;Strassman et al, 1996). The clinical manifestation of this peripheral sensitization is the throbbing nature of the migraine headache, while routine physical activity worsens the headache during migraine attacks (Goadsby, 2005).…”

Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood–brain barrier

“…Support for this has been obtained in functional tests in rodents with a CGRP antibody (Edvinsson et al, 2007). CGRP receptor antagonists, anti-CGRP and anti-CGRP receptor antibodies are currently under development (Bigal et al, 2013), and if these modalities are not able to penetrate the BBB, the trigeminal ganglion may be one site of action.…”

Anti-CGRP monoclonal antibodies in migraine: current perspectives

“…New treatment regimens, more pathophysiologically based, are, therefore, imperatively needed [6]. In this framework, the research of the last decade has focused on the crucial role played by calcitonin gene-related peptide (CGRP) in the triggering of the attacks, and as a consequence, new drugs antagonizing the effects of this peptide have been tested [7][8][9][10][11][12][13][14][15][16]. CGRP antagonists showed efficacy in several clinical trials, but their severe side effects and adverse events with long-term administration discouraged further research, and their production was thus interrupted.…”