Pituitary adenylate cyclase activating polypeptide (PACAP) and its role in migraine pathophysiology

Czech version

Authors: V. Weiss ^1,2; M. Haršány ^1,3; P. Řehulka ¹
Authors‘ workplace: I. neurologická klinika LF MU a FN u sv. Anny v Brně ¹; Neurologická klinika LF UK, Hradec Králové ²; Mezinárodní centrum klinického výzkumu, FN u sv. Anny v Brně ³
Published in: Cesk Slov Neurol N 2023; 86(3): 177-183
Category: Review Article
doi: https://doi.org/10.48095/cccsnn2023177

Overview

During the three decades of studying vasoactive substances in migraine pathophysiology, ample theoretical knowledge has been accumulated that has ushered in a groundbreaking era in migraine treatment. Pituitary adenylate cyclase activating polypeptide (PACAP) is one of these promising therapeutic targets and the subject of ongoing clinical trials. In this review article, we focus on PACAP as an endogenous signaling molecule, describing its basic properties, binding to specific receptors (PAC₁, VPAC₁, VPAC₂) and its biological activity. The latter relates to basic physiological processes of the organism (reproduction, nutrition, aging, etc.), neuroprotection in acute and chronic injury, and it is of particular importance in tissue and organ protection in ischemic stroke. The vasomotor effect of PACAP consists of cAMP-mediated relaxation of the cranial artery smooth muscle. In migraine patients, experimental application of PACAP induces vasodilation of the arteria meningea media and correlates with lateralized headache with a migrainous phenotype. Although this vasodilatation is preventable by sumatriptan, a monoclonal antibody directed against the PAC₁ receptor (AMG301) completely failed in migraine prevention. Currently, the results of clinical trials (phase 1 and 2) of monoclonal antibodies directed against PACAP (ALD1910 or Lu-AG09222, LY3451838) are eagerly awaited. If their prophylactic effect in migraine is demonstrated, this would open a new therapeutic option for patients with previously failed treatment. However, a prerequisite for potential medical use will be the demonstration of long-term safety, especially with regard to cardiovascular health.

Keywords:

cerebral blood flow – Migraine – Monoclonal antibodies – pituitary adenylate cyclase activating polypeptide – PACAP

Sources

1. Ashina M. Targeting enkephalins and pituitary adenylate cyclase-activating polypeptide (PACAP) in migraine. Brain J Neurol 2022; 145(8): 2619–2620. doi: 10.1093/ brain/ awac260.

2. Rubio-Beltrán E, Correnti E, Deen M et al. PACAP38 and PAC1 receptor blockade: a new target for headache? J Headache Pain 2018; 19(1): 64. doi: 10.1186/ s10194-018-0893-8.

3. Ashina H, Guo S, Vollesen AL et al. PACAP38 in human models of primary headaches. J Headache Pain 2017; 18(1): 110. doi: 10.1186/ s10194-017-0821-3.

4. Miyata A, Jiang L, Dahl RD et al. 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)92 140-u.

5. Rustichelli C, Lo Castro F, Baraldi C et al. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) with monoclonal antibodies in migraine prevention: a brief review. Expert Opin Investig Drugs 2020; 29(11): 1269–1275. doi: 10.1080/ 13543784.2020.1811- 966.

6. Reglodi D, Vaczy A, Rubio-Beltran E et al. Protective effects of PACAP in ischemia. J Headache Pain 2018; 19(1): 19. doi: 10.1186/ s10194-018-0845-3.

7. Schytz HW, Birk S, Wienecke T et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain J Neurol 2009; 132(Pt 1): 16–25. doi: 10.1093/ brain/ awn307.

8. Sicuteri F, Del Bene E, Poggioni M et al. Unmasking latent dysnociception in healthy subjects. Headache 1987; 27(4): 180–185. doi: 10.1111/ j.1526-4610.1987.hed2704180.x.

9. Ashina M, Hansen JM, Á Dunga BO et al. Human models of migraine – short-term pain for long-term gain. Nat Rev Neurol 2017; 13(12): 713–724. doi: 10.1038/ nrneurol.2017.137.

10. Al-Karagholi MAM, Ghanizada H, Nielsen CAW et al. Opening of ATP sensitive potassium channels causes migraine attacks with aura. Brain J Neurol 2021; 144(8): 2322–2332. doi: 10.1093/ brain/ awab136.

11. Ashina M. Migraine. N Engl J Med 2020; 383(19): 1866–1876. doi: 10.1056/ NEJMra1915327.

12. Riesco N, Pérez-Alvarez AI, Verano L et al. Prevalence of cranial autonomic parasympathetic symptoms in chronic migraine: Usefulness of a new scale. Cephalalgia Int J Headache 2016; 36(4): 346–350. doi: 10.1177/ 0333102415593087.

13. Khan S, Deen M, Hougaard A et al. Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol. Cephalalgia Int J Headache 2018; 38(5): 892–903. doi: 10.1177/ 0333102417719753.

14. Benemei S, Cortese F, Labastida-Ramírez A et al. Triptans and CGRP blockade – impact on the cranial vasculature. J Headache Pain 2017; 18(1): 103. doi: 10.1186/ s10194-017-0811-5.

15. Christensen CE, Ashina M, Amin FM. Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in migraine pathogenesis. Pharm Basel Switz 2022; 15(10): 1189. doi: 10.3390/ ph15101189.

16. Mitsikostas DD, Ashina M, Craven A et al. European Headache Federation consensus on technical investigation for primary headache disorders. J Headache Pain 2015; 17: 5. doi: 10.1186/ s10194-016-0596-y.

17. Wienholtz NKF, Christensen CE, Zhang DG et al. Early treatment with sumatriptan prevents PACAP38-induced migraine: a randomised clinical trial. Cephalalgia Int J Headache 2021; 41(6): 731–748. doi: 10.1177/ 03 33102420975395.

18. Amin FM, Asghar MS, Ravneberg JW et al. The effect of sumatriptan on cephalic arteries: a 3T MR-angiography study in healthy volunteers. Cephalalgia 2013; 33(12): 1009–1016. doi: 10.1177/ 0333102413483374.

19. Amin FM, Hougaard A, Schytz HW et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain J Neurol 2014; 137(Pt 3): 779–794. doi: 10.1093/ brain/ awt369.

20. Ashina M, Doležil D, Bonner JH et al. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia Int J Headache 2021; 41(1): 33–44. doi: 10.1177/ 0333102420970889.

21. Edvinsson JCA, Grell AS, Warfvinge K et al. Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system. Cephalalgia Int J Headache 2020; 40(12): 1296–1309. doi: 10.1177/ 0333102420929-026.

22. White TG, Powell K, Shah KA et al. Trigeminal nerve control of cerebral blood flow: a brief review. Front Neurosci 2021; 15: 649910. doi: 10.3389/ fnins.2021.649910.

23. Eftekhari S, Edvinsson L. Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 2011; 12: 112. doi: 10.1186/ 1471-2202-12-112.

24. Uddman R, Tajti J, Hou M et al. Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia Int J Headache 2002; 22(2): 112–116. doi: 10.1046/ j.14 68-2982.2002.00324.x.

25. Messlinger K. The big CGRP flood – sources, sinks and signalling sites in the trigeminovascular system. J Headache Pain 2018; 19(1): 22. doi: 10.1186/ s10194-018-08 48-0.

26. Jansen-Olesen I, Hougaard Pedersen S. PACAP and its receptors in cranial arteries and mast cells. J. Headache Pain 2018; 19(1): 16. doi: 10.1186/ s10194-017-0822-2.

27. Amin FM, Schytz HW. Transport of the pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier: implications for migraine. J Headache Pain 2018; 19(1): 35. doi: 10.1186/ s10194-018-0861-3.

28. Wiggers A, Ashina H, Hadjikhani N et al. Brain barriers and their potential role in migraine pathophysiology. J Headache Pain 2022; 23(1): 16. doi: 10.1186/ s10194-021-01365-w.

29. Šipková J, Nežádal T, Čtrnáctá D et al. Protilátky CGRP v profylaktické léčbě migrény. Cesk Slov Neurol N 2022; 85/ 118(3): 248–256. doi: 10.48095/ cccsnn2022248.

30. Kotas R, Mračková J, Potužník P. Pokrok ve znalostech patofyziologie migrény. Cesk Slov Neurol N 2022; 85/ 118(6): 451–456. doi: 10.48095/ cccsnn2022248.

31. Antonova M, Wienecke T, Olesen J et al. Prostaglandins in migraine: update. Curr Opin Neurol 2013; 26(3): 269–275. doi: 10.1097/WCO.0b013e328360.

32. Worm J, Falkenberg K, Olesen J. Histamine and migraine revisited: mechanisms and possible drug targets. J Headache Pain 2019; 20(1): 30. doi: 10.1186/s10194-019-0984-1.

33. Al-Karagholi MA, Ghanizada H, Waldorff Nielsen CA et al. Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine. Pain 2021; 162(10): 2512–2520. doi: 10.1097/j.pain.000 0000 000002238.