PACAP38 and PAC 1  receptor blockade: a new target for headache?

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Abstract

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.

Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.

Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC ₁ receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC ₁ receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.

In conclusion, the data presented in this review indicate that PACAP38 and PAC ₁ receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.

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Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.

Atsuro Miyata, Akira Arimura, Raymond R. Dahl … (1989)

A novel neuropeptide which stimulates adenylate cyclase in rat anterior pituitary cell cultures was isolated from ovine hypothalamic tissues. Its amino acid sequence was revealed as: His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln- Met-Ala- Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys - NH2. The N-terminal sequence shows 68% homology with vasoactive intestinal polypeptide (VIP) but its adenylate cyclase stimulating activity was at least 1000 times greater than that of VIP. It increased release of growth hormone (GH), prolactin (PRL), corticotropin (ACTH) and luteinizing hormone (LH) from superfused rat pituitary cells at as small a dose as 10(-10)M (GH, PRL, ACTH) or 10(-9)M (LH). Whether these hypophysiotropic effects are the primary actions of the peptide or what physiological action in the pituitary is linked with the stimulation of adenylate cyclase by this peptide remains to be determined.

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Migraine and cardiovascular disease: systematic review and meta-analysis

Markus Schürks, Pamela M Rist, Marcelo E. Bigal … (2009)

Objective To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease. Design Systematic review and meta-analysis. Data sources Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease. Data extraction Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated. Results Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk. Conclusion Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations.

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PACAP38 induces migraine-like attacks in patients with migraine without aura.

Steffen Birk, Jes Olesen, Troels Wienecke … (2008)

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

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Author and article information

Contributors

Eloisa Rubio-Beltrán:

ORCID: http://orcid.org/0000-0002-2912-3632

a.rubiobeltran@erasmusmc.nl

Edvige Correnti: edvigecorrenti@gmail.com

Marie Deen: mariedeen85@gmail.com

Katharina Kamm: Katharina.Kamm@med.uni-muenchen.de

Tim Kelderman: tim.kelderman@ugent.be

Laura Papetti: papetti.l@hotmail.it

Simone Vigneri: simone.vigneri@gmail.com

Antoinette MaassenVanDenBrink: a.vanharen-maassenvandenbrink@erasmusmc.nl

Lars Edvinsson: lars.edvinsson@med.lu.se

Journal

Journal ID (nlm-ta): J Headache Pain

Journal ID (iso-abbrev): J Headache Pain

Title: The Journal of Headache and Pain

Publisher: Springer Milan (Milan )

ISSN (Print): 1129-2369

ISSN (Electronic): 1129-2377

Publication date (Electronic): 7 August 2018

Publication date PMC-release: 7 August 2018

Publication date Collection: 2018

Volume: 19

Issue: 1

Electronic Location Identifier: 64

Affiliations

[1 ]ISNI 000000040459992X, GRID grid.5645.2, Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, , Erasmus University Medical Center, ; Rotterdam, The Netherlands

[2 ]ISNI 0000 0004 1762 5517, GRID grid.10776.37, Department of Child Neuropsychiatry, , University of Palermo, ; Palermo, Italy

[3 ]Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark

[4 ]Department of Neurology, University Hospital, LMU Munich, Munich, Germany

[5 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Department of Neurology, , Ghent University Hospital, ; Ghent, Belgium

[6 ]ISNI 0000 0001 0727 6809, GRID grid.414125.7, Headache Center, , Bambino Gesù Children’s Hospital, ; IRCCS, Rome, Italy

[7 ]ISNI 0000 0004 1762 5517, GRID grid.10776.37, Department of Experimental Biomedicine and Clinical Neurosciences, , University of Palermo; Pain Medicine Unit, Santa Maria Maddalena Hospital, ; Occhiobello, Italy

[8 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Internal Medicine, Institute of Clinical Sciences, , Lund University, ; Lund, Sweden

Author information

Eloisa Rubio-Beltrán http://orcid.org/0000-0002-2912-3632

Article

Publisher ID: 893

DOI: 10.1186/s10194-018-0893-8

PMC ID: 6081277

PubMed ID: 30088106

SO-VID: 94595ea1-b8bc-4bc4-bbc4-ab9c46c8608c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.