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`Mini-Review
`TheScientificWorldJOURNAL (2002) 2, 1484–1490
`ISSN 1537-744X; DOI 10.1100/tsw.2002.806
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`Calcitonin Gene-Related Peptide (CGRP) in
`Cerebrovascular Disease
`
`Lars Edvinsson
`Department of Internal Medicine, Lund University Hospital, S-221 85 Lund, Sweden
`
`E-mail: lars.edvinsson@med.lu.se
`
`Received April 17, 2001; Accepted April 24, 2002; Published May 30, 2002
`
`Cerebral blood vessels are innervated by sensory nerves that store several
`neurotransmitters among which calcitonin gene-related peptide (CGRP) is the
`most abundant. In primary headaches, there is a clear association between the
`head pain and the release of CGRP. In cluster headache there is an additional
`release of vasoactive intestinal peptide (VIP).
`In connection with administration of triptans, the headache subsides and the
`neuropeptide release normalises, in part via a presynaptic effect.
`In subarachnoid hemorrhage (SAH), CGRP is released to counterbalance the
`blood-induced vasospasm. In severe cases, the stored CGRP may be exhausted
`while infusion of CGRP may limit cerebral vasospasm. Thus, interactions with the
`trigeminovascular system at CGRP receptors may be a useful target for
`understanding of cerebrovascular disease and to design novel treatments.
`
`KEY WORDS: migraine, cluster headache, CGRP, subarachnoid hemorrhage, SAH,
`VIP, trigeminovascular reflex
`
`DOMAINS: neuroscience, neurology
`
`INTRODUCTION
`
`Calcitonin gene-related peptide (CGRP) is a 37–amino acid neuropeptide, first identified in
`1982[1]. It belongs to a family of peptides, which includes calcitonin, adrenomedullin, and
`amylin. Localisation studies have shown a wide distribution of CGRP immunoreactivity in the
`peripheral and in the central nervous systems[2,3]. Although CGRP-containing nerves innervate
`blood vessels in various regions, and CGRP is a potent vasodilator, it has other effects within the
`cardiovascular system and is involved in pain. The role of CGRP in the cardiovascular system is
`not well understood in normal or pathological states[3,4,5].
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`In one particular region, the cerebral blood vessels, there is a dense supply of CGRP-
`containing nerve fibres, which originate in the trigeminal ganglion[6,7]. The CGRP-containing
`cell bodies of the trigeminal system are bipolar and have functional connections with neurons in
`the trigeminal nucleus caudalis and in its related extensions down to the C11-2 level[8]. The
`peripheral part innervates intracranial vessels via its ophthalmic division. These fibres release
`CGRP following electrical stimulation[9] or capsaicin treatment[10,11] and are activated in
`primary headaches and in stroke[12]. Trigeminal fibres mediate dilatation of brain vessels[13,14],
`mediate increases in cerebral blood flow[15], and participate in the trigeminovascular reflex[13].
`The trigeminovascular system is a vasodilator pathway, which acts via antidromic release of
`CGRP upon activation[11,13] and has a primary involvement in sensory functions. Although
`CGRP has a number of effects, its most pronounced action is vasodilatation[5].
`Early studies demonstrated strong vasomotor effects of CGRP on a variety of
`tissues[3,4,5,6]. CGRP is present in two forms, α- and β-CGRP. Calcitonin and α-CGRP are
`transcribed from the same gene, while β-CGRP is formed from a duplication of the calcitonin
`αCGRP gene. Early pharmacological studies focused on the use of CGRP agonists to
`discriminate between CGRP receptor subtypes. The CGRP1 receptor was characterised as being
`particularly sensitive to antagonism by the CGRP fragment CGRP8-37, with reported pA2 values in
`the range of 1–100 nM, while the CGRP2 receptors had lower affinity for this blocker, often in
`the µM region.
`CGRP8-37 has no agonist activity at concentrations up to 10 µM. A third class of CGRP
`binding sites has been identified in the rat nucleus accumbens that recognises both α-CGRP and
`calcitonin with high affinity[16]. Subsequent cloning efforts have resulted in the molecular
`identification of the CGRP1 receptor, calcitonin receptor–like receptor (CRLR)[17]. CRLR is a
`Gs-coupled seven-transmembrane domain receptor (GPCR), which shares 55% sequence identity
`with the calcitonin receptor. McLatchie and coworkers[18] demonstrated that functional CGRP1
`and adrenomedullin receptors are both derived from CRLR and that the phenotype is determined
`by coexpression with a particular receptor activity modifying protein, RAMP. Coexpression of
`CRLR with RAMP1 results in CGRP1 receptor pharmacology while RAMP2 or RAMP3
`coexpression produces an adrenomedullin receptor. RAMPs are relatively small (148–175 amino
`acids) proteins containing a single-membrane spanning domain, a large extracellular domain, and
`a short cytoplasmic domain. The RAMPs enable expression of CRLR on the cell surface,
`determine the glycosylation state of the receptor, and determine the relative affinity of this
`receptor for CGRP and adrenomedullin[19]. CRLR internalisation following CGRP stimulation
`has been shown to occur together with RAMP1, and both proteins are targeted to the protein
`degradation pathway[20]. Although the receptors resulting from coexpression of CRLR with
`either RAMP1 or RAMP2/3 are functionally distinct and glycosylated to different extents, CGRP
`and adrenomedullin display some cross-reactivity for the opposite receptor[18]. RAMP proteins
`have, in addition, been shown to modulate the pharmacology of the calcitonin receptor, which in
`combination with RAMP1 or RAMP3, binds amylin with high affinity[21,22]. In addition to the
`RAMPs, the CGRP receptor may require another accessory protein for function, the receptor
`component protein or RCP[23].
`
`THE TRIGEMINOVASCULAR REFLEX
`
`Following the identification of the trigeminal vascular pathway and its messenger molecules[8],
`functional studies were initiated, and it was observed that denervation did not alter the regional
`cerebral blood flow or the regional cerebral metabolism, the cerebral vascular responses to carbon
`dioxide, or the cerebral autoregulation[24]. However, vasoconstrictor responses elicited by
`noradrenaline[13], alkaline pH, PGF2α, BaCl2, and subarachnoid blood[24,25] were modified.
`Following denervation, there was no alteration in the contractile response to the listed agents, but
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`the time to attain initial basal tone was markedly prolonged. Vasoconstriction triggers an
`antidromic release of sensory neuropeptides, e.g., CGRP, which normalises the vessel tone.
`Subsequent studies using neuropeptide receptor antagonists and capsaicin in combination with
`denervation showed that it is CGRP that is mainly responsible for this response[11,25].
`Vasodilation of cortical arterioles induced by acidic pH was not modified by trigeminal lesion.
`Thus, if the headache or a vasospasm is initiated by a spreading wave of depression of cortical
`neurons and/or intense vasoconstriction, the trigeminal vascular system may have a counter-
`balancing effect, resulting in a normalised vascular tone (by the release of CGRP). The activation
`of this system is noted clinically as an increase in the cranial venous outflow of CGRP during
`headache attacks or in subarachnoid haemorrhage where it was elevated also in the CSF (see
`below).
`
`NEUROTRANSMITTER RELEASE IN PRIMARY HEADACHES
`
`With a better knowledge and understanding of the organisation of the sensory nerves around the
`intracranial vessels[26], we have studied their involvement in primary headaches by analysis of
`neurotransmitter release into the cranial venous outflow[12]. In humans, stimulation of the
`trigeminal ganglion results in unilateral blood flow increases. In trigeminal neuralgia patients,
`there is, in addition, flushing on the side of stimulation, which coincides with the release of
`CGRP and substance P[9].
`In migraine attacks, there are both vascular and neurogenic components[12]. At present,
`many believe the disorder is due to mutation of a calcium channel gene rendering some central
`nervous system neurons to be unstable and capable of initiating a migraine attack. As part of the
`pathophysiological mechanisms, the trigeminovascular system is activated (putatively as a
`defense mechanism), and there is release of CGRP and activation of the trigeminal nucleus
`caudalis (TNC) with subsequent mediation of pain. The results from trigeminal ganglion
`stimulation in trigeminal neuralgia patients (neuropeptides are released and can be measured in
`the jugular vein) led us to examine the levels of various neuropeptides during migraine attacks.
`The concentrations of neuropeptide Y (NPY marker for the sympathetic nerves), vasoactive
`intestinal polypeptide (VIP, parasympathetic activity), and CGRP and substance P (markers for
`sensory nerves) were measured. There were no changes in the levels of the peptides NPY, VIP or
`substance P in the jugular vein plasma. However, a marked increase in CGRP was observed
`during migraine headache[27]. Two individuals with facial symptoms similar to those seen in
`cluster headache (e.g., nasal congestion and rhinorrhea) displayed increases in VIP. This suggests
`the involvement of a parasympathetically mediated event in these two individuals. There was no
`difference between migraine with aura or without aura.
`We propose that the release of CGRP is due to the fact that the cerebral circulation is
`preferentially innervated by CGRP-containing fibres from the trigeminal ganglion[28]. These
`observations have been confirmed in subsequent studies[29,30]. In addition, following
`sumatriptan administration, the plasma levels of CGRP returned to control with successful
`amelioration of the headache[30].
`Cluster headache is a well-described, clear-cut, clinical syndrome. Patients with episodic
`cluster headache, fulfilling the criteria of the International Headache Society, were examined
`during acute spontaneous attacks of headache to determine the local cranial release of
`neuropeptides[31]. During the attacks, the blood levels of CGRP and VIP were markedly raised,
`while there was no changes in the levels of NPY or substance P. Treatment with oxygen or
`subcutaneous sumatriptan reduced the CGRP levels to normal, while opiate administration did
`not alter the peptide levels[31]. The results show that activation of the trigeminovascular system
`and the cranial parasympathetic nervous system have a role in acute attacks of cluster headache. It
`was particularly noteworthy that all subjects responded with release of VIP. This is in concert
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`with the facial symptoms in this disorder. Furthermore, it was also shown that both oxygen and
`sumatriptan, while aborting the attacks, terminated the activity in the trigeminovascular system.
`This agrees well with the results of others[32,33] demonstrating the release of CGRP in
`nitroglycerine-elicited attacks of cluster headache. CGRP in the jugular vein on the pain side in
`cluster-headache patients was found to be elevated during the attack period and was elevated
`further at the peak of the provoked attack. There were no alterations in substance P levels.
`Interestingly, only when the subjects were in an active period was nitroglycerine able to elicit an
`attack of cluster headache[33]. This suggests that the trigeminovascular system is hyperreactive at
`this stage.
`Thus, CGRP, a marker of the trigeminovascular system, and VIP, a marker of the
`parasympathetic nerve activity, are both elevated in the cranial venous blood of patients suffering
`acute spontaneous attacks of cluster headache. The termination of the attack with either
`sumatriptan or oxygen normalised the CGRP levels, probably reflecting cessation of the activity
`in the trigeminovascular system. In contrast, administration of an opiate agonist induced pain
`relief, but did not end the trigeminovascular activity. The finding of elevated levels of both CGRP
`and VIP in the cranial venous blood during attacks suggests that there is activation of a brainstem
`reflex, the afferent arc of which is the trigeminal nerve and the efferent the cranial
`parasympathetic outflow from the VIIth nerve.
`
`SUBARACHNOID HEMORRHAGE
`
`Strong support for the involvement of this reflex in cerebrovascular disorders has come from
`studies of subarachnoid haemorrhage (SAH), both in patients and in laboratory animals. The first
`study on the involvement of perivascular sensory fibres containing substance P and CGRP in
`conjunction with subarachnoid hemorrhage (SAH) showed 2 days after blood injection, the time
`point at which maximum vasoconstriction is occurring in this model, a reduction in substance P
`and CGRP in the vessel walls immunoreactivity[34]. The quantitative measurements revealed a
`50% reduction of CGRP and only in a slight reduction of substance P in SAH as compared to
`controls. This partial reduction in neurotransmitter content caused no change in the sensitivity of
`the basilar artery to substance P or CGRP. However, the maximum relaxant response to CGRP
`was increased from 52 to 81% (p < 0.05), while there was no change in the maximum substance
`P-induced relaxations. It is suggested that not only a pre-, but also a postsynaptic modulation of
`perivascular sensory fibres may occur in experimental SAH[34].
`This was verified in a study on patients who died from SAH[35]. Their cerebral vessels were
`depleted of CGRP, but not of other neuronal messengers, indicating a selective loss of the sensory
`nerve transmitter CGRP that is putatively used to counterbalance the haemorrhage-induced
`vasoconstriction.
`In order to further learn about the possible significance of the trigeminovascular system, we
`have examined patients that have been admitted to the clinic due to an acute SAH[36,37]. After
`operation with aneurysm clipping and treatment with the calcium channel blocker nimodipine, the
`degree of vasoconstriction was monitored with Doppler ultrasound recordings bilaterally from the
`middle cerebral and internal carotid arteries. External jugular vein blood sampling for
`neuropeptides analysis was analysed every second day. The highest CGRP levels were found in
`patients with the highest velocity index values (vasospasm). In patients with middle cerebral
`artery (MCA) aneurysms, a significant correlation was found between the vasospasm index and
`the CGRP levels. There were no changes observed in the substance P or VIP levels. Alterations in
`cerebrovascular tone and in CBF, induced by changing arterial CO2 tension or by lowering of
`blood pressure (autoregulation test), did not alter the levels of the perivascular peptides[37]. In
`individual patients with marked vasoconstriction, due to SAH, increased levels of CGRP, and
`NPY were also observed in the cerebrospinal fluid (CSF), thus, complementing the venous
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`outflow peptide data. These results demonstrate that, in a strict and clearcut intracranial arterial
`vasoconstrictory disorder, the trigeminovascular reflex is activated to counterbalance vasospasm
`by release of the vasodilator CGRP. This is verified both by measurements in the jugular vein
`outflow and in the CSF. In addition, subjects that had vasospasm and cerebral ischemia were
`treated with CGRP infusion[38,39]. A multicenter study[39] could not show a significant
`beneficial effect of CGRP in this trial. The wide confidence interval for the risk of a poor
`outcome and the fact that only a third of the patients completed treatment mean that a clinically
`useful benefit could not be ruled out. Since few patients completed the study in part because of
`hypotension, we continued with another CGRP infusion study and careful monitoring[38]. The
`study was designed to evaluate the effects of intravenous administration of human α-CGRP on
`cerebral vasoconstriction in the postoperative course after SAH[38]. Cerebral vasoconstriction
`was evaluated with transcranial Dopler sonography. The increase in the relationship between
`middle cerebral artery (MCA) velocity and internal carotid artery (ICA) velocity (the
`hemodynamic index) was used as an indicator of vasoconstriction and compared to the
`contralateral side. A significant reduction was found in the hemodynamic index during the CGRP
`infusion (4.3 ± 0.5, p < 0.05) as compared to before infusion (6.2 ± 0.5). There was no
`measurable change in the hemodynamic index on the contralateral side. No significant change
`was observed in pulsatility index, blood pressure, or consciousness during the peptide infusion.
`The results obtained show that infusion of human α-CGRP may induce normalisation of
`cerebrovascular tone in SAH. Another way to increase the availability of CGRP to cerebral
`vessels in SAH is by gene transfer. This was found to be successful in the rabbit[40], proving that
`the CGRP approach may be beneficial in cerebrovascular disease.
`
`CONCLUSION
`
`CGRP seems to have a significant role in cerebrovascular disease. Adding the peptide or a
`specific molecule with agonistic effect may prove of value in SAH with vasospasm and in stroke.
`In primary headaches the novel CGRP antagonists have in clinical trials proven that they can
`ameliorate the headache and thus prove the concept. The development of further molecules in this
`field is anticipated.
`
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`This article should be referenced as follows:
`
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