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Review
. 2018 Aug 7;19(1):64.
doi: 10.1186/s10194-018-0893-8.

PACAP38 and PAC1 receptor blockade: a new target for headache?

Eloisa Rubio-Beltrán  1 , Edvige Correnti  2 , Marie Deen  3 , Katharina Kamm  4 , Tim Kelderman  5 , Laura Papetti  6 , Simone Vigneri  7 , Antoinette MaassenVanDenBrink  8 , Lars Edvinsson  9 ; European Headache Federation School of Advanced Studies (EHF-SAS)
Affiliations
Review

PACAP38 and PAC1 receptor blockade: a new target for headache?

Eloisa Rubio-Beltrán et al. J Headache Pain. .

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 PAC1 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 PAC1 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 PAC1 receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.

Keywords: Migraine; PAC1 receptor; PACAP; Prophylactic treatment.

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Conflict of interest statement

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

AMvdB received research grants and/or consultation fees from Amgen/Novartis, Lilly/CoLucid, Teva and ATI. LE has given talks and received grant for preclinical studies sponsored by Novartis and TEVA. All other authors declare no conflicts of interest.

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Figures

Fig. 1
Fig. 1
PACAP receptors. Three receptors to PACAP have been described: VPAC1, VPAC2 and PAC1. VIP and PACAP show similar affinity for VPAC1 and VPAC2, whereas PACAP is 100-fold more selective for PAC1 receptor. The antibodies developed for prophylactic antimigraine treatment bind either to PACAP (PACAP38, ALD1910) or to the PAC1 receptor (AMG 301)
Fig. 2
Fig. 2
Possible side effects after long-term exposure to PACAP (receptor)-antibodies. An overview of the organ systems where PACAP and PAC1 receptor are present and the possible side effects that could be observed
See this image and copyright information in PMC

References

    1. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun. 1989;164(1):567–574. doi: 10.1016/0006-291X(89)91757-9. - DOI - PubMed
    1. Miyata A, Jiang L, Dahl RD, Kitada C, Kubo K, Fujino M, Minamino N, Arimura A. Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) Biochem Biophys Res Commun. 1990;170(2):643–648. doi: 10.1016/0006-291X(90)92140-U. - DOI - PubMed
    1. Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, Miyata A, Jiang L, Dahl RR, Stibbs HH, Arimura A, Fujino M. A novel peptide which stimulates adenylate cyclase: molecular cloning and characterization of the ovine and human cDNAs. Biochem Biophys Res Commun. 1990;166(1):81–89. doi: 10.1016/0006-291X(90)91914-E. - DOI - PubMed
    1. Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol. 2012;166(1):4–17. doi: 10.1111/j.1476-5381.2012.01871.x. - DOI - PMC - PubMed
    1. Shinohara K, Funabashi T, Nakamura TJ, Mitsushima D, Kimura F. Differential regulation of pituitary adenylate cyclase-activating peptide receptor variants in the rat suprachiasmatic nucleus. Neuroscience. 2002;110(2):301–308. doi: 10.1016/S0306-4522(01)00479-1. - DOI - PubMed

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