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PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP

Adisa Kuburas, Bianca N. Mason, Benjamin Hing, Alyssa S. Reis, Levi P. Sowers, Cristina Moldovan Loomis, Leon F. Garcia-Martinez, Andrew F. Russo

Preprint posted on August 20, 2020 https://www.biorxiv.org/content/10.1101/2020.08.20.255968v1

Anti-PACAP monoclonal antibody can alleviate migraine in mice

Selected by Nándor Lipták

Background

Migraine is one of the most common neurological disorders in the world (Collaborators, 2018). The main symptoms are severe headache, sensitivity to sound and/or light, nausea and vomiting. The underlying mechanisms of migraine are not fully understood, but it is known that the infusion of calcitonin gene-related peptide (CGRP) or pituitary adenylate cyclase-activating polypeptide (PACAP) can induce migraine in humans. After several studies and clinical trials, which were identified CGRP as a key molecule in the pathogenesis of migraine, monoclonal antibody therapies (e.g. Galcanezumab, Erenumab, Fremanezumab, etc.) which targets CGRP receptor or CGRP have been approved by the U.S. Food and Drug Administration (FDA) in the past few years. There are ongoing or just-finished clinical trials, aiming to evaluate the effects of PACAP monoclonal-antibodies on the symptoms of migraine, but there is no approved antibody against PACAP or its receptor on the market for preventing or curing migraine. Both PACAP-27 and PACAP-38 isoforms can cause migraine-like headache in patients, but it is not clear, whether CGRP system is involved in these migraine-evoking effect of PACAP.

In this preprint, the relationship between the neuropeptides CGRP and PACAP in migraine in mice was investigated.

 

Key findings

In the discussed preprint, CD-1 mice were injected intraperitoneally (i..p.) with rat a-CGRP or PACAP-38 or PACAP-27. Antibodies (anti-PACAP monoclonal antibody or anti-CGRP monoclonal antibody or monoclonal IgG control antibody) were injected i.p. 24 h prior to peptide injections.

 

PACAP-38 responders and non-responder mice

The light aversion of mice was assessed by light/dark box, while the anxiety-like behavior was examined by open-field.

Both PACAP-38 and CGRP elicited light aversion in CD-1 mice. There was no significant difference in the anxiety-like behavior in the open field test between vehicle and PACAP-38 or CGRP treated mice. There was no significant difference between sexes. In contrast with CGRP, approximately one-third of PACAP-38 treated CD-1 mice (both males and females) had no light aversive response.

These responder and non-responder phenotypes were inheritable, and did not depend on sex.

 

Pre-treatment with anti-PACAP monoclonal antibodies

Pre-treatment with anti-PACAP monoclonal antibody attenuated the effect of both PACAP-38 and PACAP-27, but did not inhibit the CGRP-induced light aversion. Along with these findings, anti-CGRP antibody did not inhibit PACAP-28 or 27-evoked photophobia. These results indicated that PACAP might act via a CGRP-independent pathway.

 

Differences in gene expression in the trigeminal ganglia between responder and non-responder mice

RNA sequences (RNA-seq) were analyzed from 6 PACAP-38 responder and 6 non-responder mice. A total of 148 genes had significantly different mRNA expression between the two cohorts. 50 genes were more highly expressed in responder mice, including pituitary hormone and receptor mRNAs, e.g. the gonadotropin releasing hormone receptor, thyroid stimulating hormone beta (Tshb), growth hormone (Gh), and growth hormone releasing hormone receptor (Ghrhr).

 

Why I liked this preprint

Anti-CGRP monoclonal antibodies are accepted drugs for prevention migraine, but the development of other drugs is also highly needed. Anti-PACAP monoclonal antibodies might become the next effective drugs for treating migraine.

 

Questions for the authors

  1. Besides photophobia, others symptoms of migraine, such as sensitivity to sound, nausea and vomiting could impair the quality of life of patients as well. May anti-PACAP monoclonal antibody prevent those symptoms of migraine in mice or human patients?
  2. Galcanezumab, Erenumab and Fremanezumab are administrated subcutaneously (s.c.) to human migraine patients. In addition, anti-PACAP monoclonal antibodies, ALD 1910 and AMG 301 have been injected s.c. or intravenously (i.v.) in recent clinical trials. Why did you choose i.p. injection over s.c. injection in your experiments?
  3. Transgenic mice were created for modelling human familial hemiplegic migraine (e.g. van den Maagdenberg et al., 2010; Chanda et al., 2013). According to your data, would anti-PACAP monoclonal antibody be effective in alleviating migraine in these transgenic mice?

 

References

Collaborators GBDH (2018) Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:954-976. Doi: 10.1016/S1474-4422(18)30322-3

van den Maagdenberg et al. (2010) High Cortical Spreading Depression Susceptibility and Migraine-Associated Symptoms inCaV2.1 S218L Mice. ANN NEUROL 67:85–9.

Doi: 10.1002/ana.21815

Chanda et al (2013) Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. Pain 154, (8), 1254-1262, Doi: 10.1016/j.pain.2013.03.038

 

Posted on: 10th September 2020 , updated on: 25th January 2021

doi: https://doi.org/10.1242/prelights.24565

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Author's response

Prof. Andrew F. Russo shared

Thank you again for selecting out paper. In answer to your queries, see below.

1.Besides photophobia, others symptoms of migraine, such as sensitivity to sound, nausea and vomiting could impair the quality of life of patients as well. May anti-PACAP monoclonal antibody prevent those symptoms of migraine in mice or human patients?

Good question, I expect that they will but I do not know. My hunch is based on the efficacy of other migraine drugs that have blocked both the pain and associated symptoms. However, that remains to be tested.

2.Galcanezumab, Erenumab and Fremanezumab are administrated subcutaneously (s.c.) to human migraine patients. In addition, anti-PACAP monoclonal antibodies, ALD 1910 and AMG 301 have been injected s.c. or intravenously (i.v.) in recent clinical trials. Why did you choose i.p. injection over s.c. injection in your experiments?

Good point. Initially I wanted to inject the mice in the same way that CGRP was given to people (i.v.). The clinical trials with people using small molecule antagonist (early gepants) had either used i.v. or oral administration. However, i.v. injections in mice are difficult to do and very stressful to the mice. And oral gavage of a peptide or antibody is not an option. The clinical trials with antibodies using s.c. were still far in the future. While we thought of s.c. back in the early days, at the time we had experience with i.p. for other projects, so I chose to stick to what we could do in the lab that was minimally invasive to the mice.

3.Transgenic mice were created for modelling human familial hemiplegic migraine (e.g. van den Maagdenberg et al., 2010; Chanda et al., 2013). According to your data, would anti-PACAP monoclonal antibody be effective in alleviating migraine in these transgenic mice?

Again, great question. I do not think so, but of course the experiments have to be done. My reason for skepticism is that CGRP does not appear to be a major player in those models, and given the similarities between CGRP and PACAP, I suspect that PACAP will also not be a major player for FHM or other rare familial migraines. But again, we need to do the experiments.

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