Both clinical and physiological consideration of migraine suggests that the pathophysiology of the syndrome is intimately linked to the trigeminal innervation of the cranial vessels, the trigeminovascular system. Studies were conducted on cats and humans to examine the interaction of these systems with the effective acute antimigraine drugs dihydroergotamine and sumatriptan. In the animal studies cats were anesthetized and prepared for routine physiological monitoring as well as for blood sampling from the external jugular veins. Cerebral blood flow was monitored continuously using laser Doppler flowmetry and the effect of trigeminal ganglion stimulation on both cerebral blood flow and jugular vein peptide levels determined prior to and after administration of either sumatriptan or dihydroergotamine. Stimulation of the trigeminal ganglion led to a frequency-dependent increase in cerebral blood flow, with a mean maximum of 43 ± 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine. Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene–related peptide (CGRP), with the level rising from 67 ± 3 to 82 ± 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by both sumatriptan and dihydroergotamine. Human studies were conducted as part of the overall evaluation of sumatriptan for the treatment of acute migraine. In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 ± 8 pmol/liter) were normalized, with the headache being relieved (40 ± 8 pmol/liter). These data characterize some aspects of the cerebrovascular physiology of the trigeminovascular system and demonstrate important interactions between this system and the effective antimigraine agents sumatriptan and dihydroergotamine and that such interactions can be represented in animal models.

The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats

https://pure.rug.nl/ws/files/14697409/2001ProgNeurobiolFarkas.pdf

Cerebral microvascular pathology in aging and Alzheimer's disease.

This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM). CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas. They share vasodilator activity, albeit to varying extents depending on species and tissue. In particular, CGRP has potent activity in the cerebral circulation, which is possibly relevant to the pathology of migraine, whilst vascular sources of AM contribute to dysfunction in cardiovascular disease. Both peptides exhibit potent activity in microvascular beds. All three peptides can act on a family of CGRP receptors that consist of calcitonin receptor-like receptor (CL) linked to one of three receptor activity-modifying proteins (RAMPs) that are essential for functional activity. The association of CL with RAMP1 produces a CGRP receptor, with RAMP2 an AM receptor and with RAMP3 a CGRP/AM receptor. Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented. The cardiovascular activity of these peptides in a range of species and in human clinical conditions is detailed, and potential therapeutic applications based on use of antagonists and gene targeting of agonists are discussed.

https://www.physiology.org/doi/pdf/10.1152/physrev.00037.2003

Vascular Actions of Calcitonin Gene-Related Peptide and Adrenomedullin

The retinal and cerebral microvasculatures share many morphological and physiological properties. Assessment of the cerebral microvasculature requires highly specialized and expensive techniques. The potential for using non-invasive clinical assessment of the retinal microvasculature as a marker of the state of the cerebrovasculature offers clear advantages, owing to the ease with which the retinal vasculature can be directly visualized in vivo and photographed due to its essential two-dimensional nature. The use of retinal digital image analysis is becoming increasingly common, and offers new techniques to analyse different aspects of retinal vascular topography, including retinal vascular widths, geometrical attributes at vessel bifurcations and vessel tracking. Being predominantly automated and objective, these techniques offer an exciting opportunity to study the potential to identify retinal microvascular abnormalities as markers of cerebrovascular pathology. In this review, we describe the anatomical and physiological homology between the retinal and cerebral microvasculatures. We review the evidence that retinal microvascular changes occur in cerebrovascular disease and review current retinal image analysis tools that may allow us to use different aspects of the retinal microvasculature as potential markers for the state of the cerebral microvasculature.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-7580.2005.00395.x

Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. 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 they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant 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. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

CGRP as the target of new migraine therapies — successful translation from bench to clinic

Calcitonin gene-related peptide (CGRP) is a neurotransmitter candidate together with the tachykinins in sensory fibres in the cerebral vasculature, with possible vasodilating properties. The origin of most of the CGRP-immunoreactive cerebrovascular nerve fibres seems to be the trigeminal ganglion. Experimentally produced vasoconstriction in cats after lesions of the trigeminal ganglion have shown marked prolonged constriction compared to controls. The possible involvement of the trigemino-cerebrovascular system as a defence system, with CGRP probably being the more potent vasodilatator, was investigated in 12 patients with subarachnoid haemorrhage (SAH). After operation with clipping of the aneurysm and treatment according to department policy, blood samples were taken from the external jugular vein on postoperative days 1, 2, 3, 5, 7, 9, frozen and analysed (radioimmunoassay) for CGRP-LI (-like immunoreactivity) levels. The patients were monitored with Doppler recordings from the middle cerebral arteries (MCA) and internal carotid arteries (ICA) following blood sampling. The relationship Vmean MCA/V mean ICA was used as an index of vasospasm. The highest CGRP-LI levels were found in the patient with highest velocities/index values. In patients with MCA aneurysms (n = 7), a correlation of r = 0.61 was found between the index and CGRP-LI levels. However, significant changes in the group as a whole was not found. The possible involvement of the trigemino-cerebrovascular system in SAH is discussed.

Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man. Signs of activation of the trigemino-cerebrovascular system?

A possible involvement of perivascular vasodilatory neuropeptides in subarachnoid haemorrhage (SAH) has been evaluated in man by measuring the levels of calcitonin gene related peptide (CGRP)-, substance P (SP)- and vasoactive intestinal peptide (VIP)-like immunoreactivity (LI) in the cranial venous outflow and in CSF in 34 patients admitted to the hospital after an acute SAH.

Alterations in Perivascular Dilatory Neuropeptides (CGRP, SP, VIP) in the External Jugular Vein and in the Cerebrospinal Fluid Following Subarachnoid Haemorrhage in Man

Calcitonin gene-related peptide (human α-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage

INTRODUCTION--Cerebral blood vessels are innervated by sympathetic nerve fibres storing neuropeptide Y (NPY), parasympathetic nerves storing acetylcholine, vasoactive intestinal peptide (VIP) and sensory afferent fibres containing calcitonin gene-related peptide (CGRP), substance P (SP) and neurokinin A. In experimental studies on subarachnoid haemorrhage (SAH) there are indications that perivascular peptides are involved. In the present study we have in man measured the levels of NPY, VIP, SP and CGRP in brain vessels of patients that have suffered a fatal SAH and compared this with the levels encountered in subjects that died of an extracerebral cause. MATERIAL AND METHODS--Vessels from patients who have died from SAH or nonSAH were obtained during autopsy performed within 24 hrs after death. The peptides were extracted and fractionated with reversed phase liquid chromatography (HPLC). The levels of NPY, VIP, SP, and CGRP were measured with radioimmunoassay. Vasomotor responses of human cerebral arteries were performed using a sensitive in vitro system. RESULTS--Human cerebral vessels contained NPY, VIP, CGRP and SP which eluted at the same positions as the authentic peptides. The level of CGRP was significantly lower (p < 0.01) in arteries removed from SAH patients as compared to control subjects. The level of SP was not changed, if anything it tended to be increased after SAH. The levels of NPY and VIP were not significantly altered after SAH. In isolated brain vessels alpha-CGRP was a potent vasodilator of arteries precontracted with whole blood, prostaglandin F2 alpha or endothelin. It had a poor effect on vessels precontracted with 60 mM potassium. CONCLUSION--The evidence suggest that the trigemino-cerebrovascular system, storing CGRP and SP, is to a differential degree involved in the pathophysiology of SAH in man and supports the hypothesis of an exhaustion of CGRP as one important factor in the development of late spasm occurring after SAH.

Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage

The present paper reviews recent studies in monkey and man adding further to understanding of the role of perivascular peptides in the pathophysiology of subarachnoid haemorrhage. 1. The perivascular fibers, sympathetic fibers (storing noradrenaline, neuropeptide Y), parasympathetic fibers (storing acetylcholine, vasoactive intestinal peptide, peptide histidine methionine and neuropeptide Y) and sensory fibers (storing tachykinins, calcitonin gene-related peptide) were traced using True Blue in monkey. 2. Tracing studies of the monkey middle-cerebral artery (MCA) innervation confirmed earlier studies in rats and cats, with superior cervical and trigeminal ganglia as main immunostaining areas, and contralateral involvement in the superior cervical and trigeminal ganglia. Sphenopalatine immunostaining was scarce. 3. The release of neuropeptides in the external jugular vein in humans in the postoperative course after subarachnoid hemorrhage, using radioimmunoassay, was correlated to hemodynamical changes (vasoconstriction) monitored with Doppler ultrasound on middle cerebral (MCA) and internal carotid arteries (ICA)). 4. Neuropeptide Y-like immunoreactivity (NPY-LI) levels were increased compared to controls in patients with hemodynamic changes, and in some patients a relationship was found between velocities and NPY-LI. 5. Calcitonin gene-related peptide-LI levels were also increased in connection with vasospasm. In patients with MCA lesions a correlation of 0.61, p = 0.0002 was found between hemodynamic index (V MCA/V ICA) and CGRP-LI. The possible sympathetic and trigemino-cerebrovascular activation are discussed.

Roar Juul

Papers

Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man. Signs of activation of the trigemino-cerebrovascular system?

Alterations in Perivascular Dilatory Neuropeptides (CGRP, SP, VIP) in the External Jugular Vein and in the Cerebrospinal Fluid Following Subarachnoid Haemorrhage in Man

Calcitonin gene-related peptide (human α-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage

Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage

Peptidergic innervation of the cerebral circulation. Role in subarachnoid hemorrhage in man.