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

Rubio-Beltrán, Eloisa ; Correnti, Edvige ; Deen, Marie ; Kamm, Katharina ; Kelderman, Tim ; Papetti, Laura ; Vigneri, Simone ; MaassenVanDenBrink, Antoinette and Edvinsson, Lars LU (2018) In The journal of headache and pain 19(1).
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Migraine, PAC1 receptor, PACAP, Prophylactic treatment
in
The journal of headache and pain
volume
19
issue
1
pages
1 pages
publisher
Springer
external identifiers
  • pmid:30088106
  • scopus:85055601743
ISSN
1129-2369
DOI
10.1186/s10194-018-0893-8
language
English
LU publication?
yes
id
628a197f-e219-46ec-abaf-870ca769660e
date added to LUP
2018-11-19 11:26:35
date last changed
2020-07-08 04:33:28
@article{628a197f-e219-46ec-abaf-870ca769660e,
  abstract     = {<p>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.</p>},
  author       = {Rubio-Beltrán, Eloisa and Correnti, Edvige and Deen, Marie and Kamm, Katharina and Kelderman, Tim and Papetti, Laura and Vigneri, Simone and MaassenVanDenBrink, Antoinette and Edvinsson, Lars},
  issn         = {1129-2369},
  language     = {eng},
  month        = {08},
  number       = {1},
  publisher    = {Springer},
  series       = {The journal of headache and pain},
  title        = {PACAP38 and PAC<sub>1</sub> receptor blockade : a new target for headache?},
  url          = {http://dx.doi.org/10.1186/s10194-018-0893-8},
  doi          = {10.1186/s10194-018-0893-8},
  volume       = {19},
  year         = {2018},
}