Headache Medicine 2020, 11(3):61-67 ISSN 2178-7468, e-ISSN 2763-6178
61
ASAA
DOI: 10.48208/HeadacheMed.2020.18
Headache Medicine
© Copyright 2020
Review
CGRP: from history to clinical application - A review
Afonso Henrique Aragao, Joel Sanabria Duarte, Daniel Benzecry Almeida, Ricardo Ramina
Instituto de Neurologia de Curitiba, Neurocirurgia,Curitiba, Parana, Brazil
Abstract
The role of calcitonin gene-related peptide (CGRP) and its receptor have played an important
role in migraine for the last decades due to development of therapies that target their receptors at
the trigeminal pain system, aiming at prevention or relief of acute migraine attacks. At rst, CGRP
receptor antagonists, called gepants have demonstrated appropriate effectiveness. In addition,
they did not cause vasoconstriction, one of the drawbacks of triptans. However, their use had to be
discontinued due to the risk of liver toxicity. Humanized monoclonal antibodies towards CGRP and
the CGRP receptor have been developed as an alternative approach to block CGRP transmission.
Still, there are some questions not fully answered as where CGRP and its receptor are located, how
they inuence the mechanisms of migraine attacks and if the blood brain barrier has any sort of
importance. There is still much to learn about CGRP and migraine pathophysiology, especially its
anatomical target sites and anti-CGRP agents. This paper presents a review of CGRP, including a
brief history, focusing in CGRP mechanism, updates and future treatments.
Afonso Henrique Aragao
afonsoaragao3@gmail.com
Edited by
Mario Fernando Prieto Peres
Headings:
Calcitonin Gene-Related Peptide
Headache
Migraine with aura
Migraine without aura
Received: July 27, 2020
Accepted: September 30, 2020
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Aragao AH, Duarte JS, Almeida DB, Ramina R
CGRP: from history to clinical application - A review
Introduction
M
igraine is one of the oldest known diseases. The rst
report of migraine treatment comes from Egyptian
medicine, about 4,000 years ago (Migraine - paradigm
shift). The famous doctor Ibn Sina (Avicenna), born in 980, in
the city of Bukhara (Uzbekistan) at his time already described
local treatments for migraine, such as application of local
anesthetic in the temporal region (Avicenna). The treatment of
migraine has evolved over the years and, nowadays, molecu-
lar therapies have assumed an important role in this disease
1
.
Actually, migraine is the third most prevalent disease in the
world
2
, and is also the third leading cause of disability in
people under 50 years of age.
2
Classically, migraine can be divided in different subtypes
- migraine with aura and migraine without aura. However,
a third type can be described according to the number of
attacks per month - chronic migraine.
3
The denition of migraine with aura (or classic migraine) is
that of recurrent attacks lasting for minutes, of completely
reversible neurological symptoms, such as visual, sensory or
other symptoms from the central nervous system, which usually
develop gradually and are usually followed by headache as
well as other migraine symptoms (International Classication
of Headache - third edition). It is worth mentioning that the
aura usually lasts <60 minutes and that, if the duration is
longer than this period, another diagnosis must be taken
into account.
3
Migraine without aura (or common migraine) is also a recur-
rent headache with attacks lasting from 4 hours to 72 hours,
with unilateral, pulsatile, moderate to severe pain associated
with nausea and/or photophobia and phonophobia, whose
exacerbation of pain is caused by routine physical activity.
3
Chronic migraine, on the other hand, can be dened as a
headache that occurs on 15 days or more days per month
for a period longer than 3 months, with at least 8 days per
month of migraine headache - with or without aura.
3
For the treatment of these conditions, CGRP (calcitonin
gene-related peptide) and its receptor have gained an import-
ant eld in the last decades, which is the focus of this article.
History
CGRP is a 37-amino acid neuropeptide and a potent endoge-
nous vasodilator. It was rst described in 1982 at the Univer-
sity of California by Ronald M. Evans, Susan G. Amara and
his collaborators
4
and has since assumed an important role
in studies addressing the trigeminovascular system. In 1985,
Lars Edvinsson suggested that CGRP would be important in
the regulation of cerebral blood ow and, consequently, in
migraine.
5
In 1988 with Goadsby et al.
6
the rst study emerged that
brought evidence that CGRP is increased in classic migraine
(with aura) and common migraine (without aura) attacks to
the detriment of other neuropeptides, thus suggesting CGRP
as a therapeutic target in this condition. In the early 90s,
triptans gained an important role in the treatment of migraine.
Three years after that article, these same authors showed that
sumatriptan prevented the increase in plasma CGRP while
aborting headache attacks.
7
In 1998 Linda M. McLatchie and Steven M. Foord and other
collaborators promoted the characterization of the compo-
nents of the CGRP receptor, which consists of CALCRL, RAMP1
and RCP - these will be covered in the subsequent topics.
8
In 2000, a study published by a German team carried out
the characterization of olcegepant (BIBN4096BS), the rst
blocker of the CGRP receptor.
9
Four years later, the study by
Olesen et al.
10
showed that the intravenous infusion of olce-
gepant promoted relief of headache and improved functional
capacity in patients with migraine (with or without aura). A
year later, in 2005, the German industry Merck registered the
patent for the use of anti-CGRP antibodies to treat migraine.
In the following years, trials involving anti-CGRP antibodies
were developed, the main target of which was the use of
medications for the prophylaxis of migraine attacks (galcane-
zumab, eptinezumab, fremanezumab, erenumab). However,
it was only in 2018, 36 years after the description of the
CGRP by Amara et al.
11
that the rst drug, erenumab, was
approved for use in the prevention of episodic migraine (<15
episodes/month).
CGRP peptide
The CGRP is a peptide that act as neurotransmitter and is
produced in sensory neurons and numerous sites throughout
the CNS. CGRP is produced in α and β forms. Seeing that
the β form is not found in some species, the α form has been
more studied. It is a 37-amino-acid peptide, produced through
alternative splicing of RNA transcript from the calcitonin gene
(located in chromosome 11) that results in production of dis-
tinct mRNAs encoding this peptide.
4,12
CGRP is generated as
a pro-peptide, with endogenous cleavage sites and is broken
63
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Aragao AH, Duarte JS, Almeida DB, Ramina R
CGRP: from history to clinical application - A review
down by metalloproteinases.
13
With amidation of the carboxyl
terminus it is less susceptible to degradation by proteases
increasing its half-life. Afterwards, the peptides are packaged
into storage vesicles transported to be released in the pre-
synaptic terminals via calcium- dependent exocytosis.
14
CGRP
release can be stimulated by capsaicin, while studies show
that this constituent of some red peppers that has been useful
as an experimental tool to deplete CGRP from its release site.
15
Presynaptic receptors are located on trigeminal neurons where
they regulate CGRP release. These are serotonin (5-hydroxy-
tryptamine) 5-HT1B and 5-HT1D receptors, which play an
important role in pathophysiology of migraine, since that when
activated, they inhibit CGRP release.
7
Triptans are used directed
to these receptors in order to treat acute migraine episodes. In
2017, the 5-HT1F receptor was identied as a target of interest
in CGRP release suppression.
16,17
The specic 5-HT1F agonist
lasmiditan, has efcacy as a treatment for acute migraine
attacks and could serve as a treatment option for patients with
a cardiovascular risk, based on its lack of vasoconstriction.
Further limitations include CNS adverse event prole due to its
fast penetration through the blood brain barrier.
18
Studies suggest that after stimulation or coagulation of trigem-
inal ganglion, CGRP is released and can be measured in
external jugular vein blood samples. In the same way, patients
who had CGRP levels increased had ushed, suggesting that
CGRP is spillover in blood from sites of neuronal release.
6
A study to describe CGRP pharmacokinetics after infusion
of CGRP estimated the plasma half-life between 7-26 min,
depending on decay speed. Furthermore, this study showed
the reduction of gastrointestinal hormones concentration.
19
CGRP receptor and signaling
The CGRP is a member of the calcitonin/CGRP family of
peptides (which includes calcitonin, α and β CGRP, amylin,
adrenomedullin (AM) and adrenomedullin 2/intermedin
(AM2/IMD), all of them act at class B G protein-coupled
receptors (GPCRs). The calcitonine receptor-like receptor (CLR)
act as main part of this protein complex.
20
In order to have
specic afnity and functionality this protein is associated
with a receptor activity modifying protein 1 (RAMP1), these
single transmembrane protein also alter pharmacology and
cell trafcking of this complex.
8
In addition, the CLR/RAMP1 complex is coupled to a third
cytoplasmatic protein named CGRP-receptor component pro-
tein (RCP) in order to improve signaling and CGRP efcacy
by amplifying G protein activation.
CLR is coupled to a G protein that contains the G. subunit,
which activates adenylyl cyclase and cAMP- dependent
signaling pathways. Intracellular cAMP activate protein kinase
A (PKA), which results in the phosphorylation of multiple
targets
12
: including opening of potassium sensitive ATP chan-
nels (KATP channels), leading to vasodilation
21
, extracellular
signal-related kinases (ERKs) involved in protective pathways
against apoptosis and transcription factors such as cAMP-re-
sponsive element-binding protein (CREB) indicating that CGRP
is able to affect gene transcription.
22,23
In cerebrovascular
smooth muscle, elevation of cAMP upon CGRP activation
results in vasorelaxation and dilation of the blood vessel.
5
CGRP has also been shown to mediate endothelial-dependent
vasodilation involving cAMP and a positive inuence on the
nitric oxide pathway in protection against aortic vascular
hypertrophy and brosis in a model of hypertension.
24,25
Endothelin converting enzyme-1 (ECE-1) is a metalloendopep-
tidase, being in early endosomes to degrade CGRP. After
transient stimulation, CGRP co-internalizes with CLR, RAMP1,
β-arrestin2 and ECE-1 to early endosomes. CGRP degradation
promotes CLR/RAMP1 recycling and β-arrestin2 redistribution
to the cytosol. Chronic exposure to CGRP initiates an inter-
nalization process that trafcks the receptor to lysosomes for
degradation, probably as a desensitization mechanism.
26
Interestingly, there is a receptor that responds equally well to
amylin and CGRP, the amylin receptor AMY1, which consists
of RAMP1 and the calcitonin receptor (CTR), another type
of another type of GPCRs from the calcitonin/CGRP family
(20). Although AMY1 was found in rats trigeminal ganglion,
it appears to have a lesser role as is not blocked by drugs
that target the CGRP receptor.
27
Trigeminovascular system
The trigeminovascular system is involved in the regulation of
the cranial vasculature and is a key element in transmission
of pain. Immunohistochemical staining with anti- CGRP
antibodies and in situ hybridization to localize CGRP mRNA
have shown that approximately half of all neurons in the
trigeminal ganglion express CGRP.
1–3
CGRP positive neurons
were predominantly found in in C-type sensory pain bers.
In the other hand, CGRP receptor components were detected
in larger neurons with thicker bers which correspond to Aδ-
sensory neurons, this could facilitate interaction between
sensory nerves to amplify nociceptive signaling.
4
Also, CGRP
receptors were found at satellite glial cells organized around
neuronal cell bodies, this proximity suggests that neuron-glia
communication exists, as some studies reveal. CGRP release
activates inammatory cytokines and nitric oxide liberation
from glia cells and these substances enhance CGRP release
64
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Aragao AH, Duarte JS, Almeida DB, Ramina R
CGRP: from history to clinical application - A review
creating a positive feedback within the ganglion.
3,5 –11
5-HT
1B
and 5-HT
1D
receptors are expressed in the human
trigeminal ganglion and they are mainly in medium-sized
cells colocalized with CGRP. This relation suggests that
triptans regulates CGRP release via inhibition of those
receptors.
12,13
Staining of CGRP and SNAP-25 (a presynaptic nerve
terminal protein that has a role in synaptic vesicle fusion
and exocytosis), showed coexpression in thin nerve bers
proximal to trigeminal ganglion cell bodies, suggesting
paracrine signaling.
14
Trigeminal peripheral targets
CGRP was found in perivascular trigeminal terminations,
located at the adventitial vessel walls. After release, CGRP
increases intracellular cAMP decreases intracellular Ca
2+
,
relaxing cerebral arteries with no effect on veins.
28,29
Interestingly, this peptide has no effect in endothelium.
This was described in a study when after removing the
endothelium the relaxation persisted.
5
In addition, in other
study to examine the role of the endothelial barrier of brain
vessels, luminal CGRP was applied with relaxation response.
However luminal CGRP had minor effects on arteries. This
suggests that the endothelium act as a barrier, conrmed
with no response on vessels diameter after CGRP antagonist
luminal administration.
30,31
Regardless, a study concluded
that infusion of human CGRP may alter vasoconstriction in
SAH. The CGRP role in the trigeminovascular vasodilatory
reex in vasoconstriction has also been described as
a protective brain circulation response. After chronic
trigeminal system lesion, perivascular CGRP disappeared
and arteriolar response to noradrenaline vasoconstrictor
was prolonged.
29
Another key point to explain CGRP mechanism, is the
presence of CGRP receptors in the smooth muscle of middle
meningeal, middle cerebral, pial, and supercial temporal
vessels where CGRP act to cause vasodilation.
10,32,33
Interestingly, no endothelial barrier is present in these
vessels, allowing CGRP antagonists to act. It is known that
activation of the trigeminovascular system by chemical
stimulation of the dura also activates perivascular sensory
bers, leading to hypersensitivity to mechanical and thermal
stimuli.
34,35
Likewise, experiments made after application of
pain-inducing substances into the dura, induced enhanced
expression of CGRP and activation of trigeminal ganglia
unmyelinated bers.
15
However, current studies seems to
focus more on the neural mechanism of migraine trigger
factors rather than on dural theories, since the dura mater
does not seem to be the primary target to CGRP-target
therapies
11,3 6
Nevertheless, this cannot be ruled out, due to
the absence of endothelial barrier on this structure to this
drugs act.
Trigeminal central targets
It is very important to identify the regions of the central
nervous system that process nociceptive information from
the trigeminovascular system. Immunohistochemistry studies
showed the highest density of CGRP immunoreactive
thin bers were found at the Spinal Trigeminal Nucleus
(STN) supercial laminae while CLR and RAMP 1 where
predominantly found at the spinal trigeminal tract region, no
colocalization was noted. In C1, CGRP was expressed in
thicker bers of laminae I and II, receptor components where
found in the same site but in different bers. Interestingly
no cell bodies where positive, suggesting that CGRP acts to
modify A-delta bers.
37
Other recent study investigating CGRP neuropeptide
location, related to pain processing and others functions,
showed immunoreactivity in most of the neurons of the
cerebral cortex, hippocampus, cerebellum, thalamic nuclei,
hypothalamic nuclei and brainstem nuclei.
38
In this way, In
situ hybridization and immunouorescence were performed
to detect mRNA expression of RAMP1 and CLR, mRNA
and protein expression were detected in the pineal gland,
medial mammillary nucleus, median eminence, infundibular
stem, periaqueductal gray, area postrema, pontine raphe
nucleus, gracile nucleus, spinal trigeminal nucleus, and
spinal cord.
39
The reduced passage into the brain of some
drugs as gepants and antibodies, limits the possibility of the
CNS as the main site of therapeutic target as no effective
drug level is reached, so they could act outside the CNS.
40
Table 1. Main sites of CGRP molecule and CGRP receptor
CGRP MOLECULE CGRP RECEPTOR
• C-bre trigeminal neuron
(spinal trigeminal nucleus
supercial laminae)
• C1, C2 laminae I and II
of the dorsal horn
• Cerebral cortex,
hippocampus,
cerebellum, thalamic
nuclei, hypothalamic
nuclei.
• A-delta ber trigeminal neuron
• Trigeminal ganglion satellite glia
• Spinal Trigeminal tract region
• Smooth muscle vessels (middle
meningeal, middle cerebral, pial
and supercial temporal vessels)
• Pineal gland, medial
mammillary nucleus, median
eminence, infundibular stem,
periaqueductal gray, area
postrema, pontine raphe
nucleus, gracile nucleus.
CGRP related therapies
Currently, there are four drugs developed (or in the nal stages
of development), which work in the CGRP pathway (Table 2).
65
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CGRP: from history to clinical application - A review
Erenumab (trade name Aimovig®) was evaluated in a study
with 667 patients (placebo: 286, Erenumab 70 mg: 191,
Erenumab 140 mg: 190). The use of Erenumab reduced
the number of migraine attack days per month by 6.6 days
(at doses of 70 mg and 140 mg) while the placebo group
reduced it by 4.2 days. In the last 4 weeks of patient evalu-
ation, 40% of the patients in the 70 mg group and 41% of
the patients in the 140 mg group showed a 50% or more
reduction in the number of migraine days per month, while
in the placebo group only 23% showed such a reduction.
The incidence of side effects was 39% in the placebo group,
44% in the 70 mg group and 47% in the 140 mg group. The
most commonly reported adverse effects were pain at the
injection site, upper airway infection, nausea, pharyngitis,
constipation, muscle and migraine spasms.
41
Fremanezumab (brand name Ajovy
®
) was evaluated in a
study with 264 patients. In the study, doses of the drug (or
placebo) were given every 28 days (one cycle) for 3 months
(total of 3 cycles). Of these patients, 89 were randomized to
receive placebo; 88 patients were selected for the 675/225
mg group (in which they received 675 mg in the rst cycle
and in the subsequent 2 cycles 225 mg); and 87 for the
900 mg group (in which they received 900 mg doses in the
3 cycles). During the last follow-up of the study (weeks 9 to
12), the reduction in the number of hours with headache was
measured: the 675/225 mg group had an average reduction
of 59.84 hours; the 900 mg group had an average reduc-
tion of 67.51 hours and the placebo group had an average
reduction of 37.10 hours. The most common adverse events
were pain at the injection site and itching. 40% of the patients
in the placebo group, 53% in the 675/225 mg group and
48% of the patients in the 900 mg group had some type
of adverse effects (42). More recently, Fremanezumab was
evaluated in another study with 1,130 patients, who were
divided into 3 groups and evaluated for 3 months – the rst
group with 376 patients, received a single dose of 675 mg
at the beginning of treatment and then only placebo; the
second group (379 patients) received a dose of 675 mg at
the beginning of treatment and then two more doses of 225
mg (one each month); and nally, a third group (375 patients)
who received only placebo. The percentage of patients who
experienced a reduction of at least 50% in the average
number of days with headache per month was 38% in the
group that received a single dose of Fremanezumab 675 mg,
41% in the group that received the medication monthly and
18% in the placebo group. Regarding adverse effects, 70%
of the patients in the group that received the 675 mg dose
(in a single dose) had at least one adverse effect, 71% of the
patients in the group that received the medication monthly
and 64% of the patients that received only placebo had at
least one side effect. Injection site pain was the most common
effect reported in all groups.
43
In relation to Eptinezumab, the company Alder
®
recently
released the results of the phase 3 study PROMISE 2 (Pre-
vention Of Migraine via Intravenous Eptinezumab Safety and
Efcacy-2 Trial), in which 1072 patients were evaluated and
randomized into 3 groups – the rst group received a single
dose of 300 mg of Eptinezumab every 12 weeks (for a total
of two applications), the second group received 1 dose of
100 mg of the medication every 12 weeks (for a total of two
applications) and the third group received only placebo. In
the 300 mg group, the reduction in the number of days with
headache in the month was 8.8 days at the end of the sixth
month. In the 100 mg group this reduction was 8.1 days, while
in the placebo group it was 6.1 days at the end of month
6. The side effects most related to Eptinezumab are upper
respiratory tract infection and dizziness.
44
Galcanezumab
®
was evaluated in a study with 1,113 patients
– 558 patients received a placebo, 278 patients received a
120 mg monthly dose (with an initial dose of 240 mg – a total
of 3 applications at the end of the 3 months), 277 patients
received 240 mg monthly (3 applications at the end of 3
months). During the 3 months of treatment, the average rate
of patients with ≥50% and ≥75% reduction from baseline
in the number of days with headache per month were higher
at both doses of galcanezumab than placebo; 27.6% (from
the 120 mg group) and 27.5% (from the 240 mg group) of
patients showed ≥50% improvement in the number of days
with headache per month while the placebo group showed
an improvement of 15.4%.
45
Conclusion
The development of drug therapies for the treatment of head-
ache has evolved greatly in recent decades. It is known that
when there are several therapeutic modalities available for
a given disease, what is true is that none of them is 100%
effective. In the case of migraine it is no different. On the other
hand, understanding the CGRP pathway and the develop-
ment of therapies that work in this system is of fundamental
importance for the treatment of migraine sufferers. The fact
that the medications that act on the CGRP pathway did not
promote the "cure of migraine" reinforces the theory - already
well known - that the origin of pain is multifactorial and that
this patient's approach must be multidisciplinary. Although we
have not yet found the “cure”, we have gained an ally in the
therapeutic arsenal to approach migraine sufferers.
Conflicts of Interest: The authors declare no conicts of interest.
Contribution: AHA - Original Conceptualization, Writing and Prepa-
ration, JSD - Original Writing and Preparation, DBA - Project Man-
agement, Supervision, RR - Supervision
Financing: No
66
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CGRP: from history to clinical application - A review
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