Abstract
Migraine is one of the most common of neurological disorders with a
global prevalence of up to 15%. One in five migraineurs have frequent
episodic or chronic migraine requiring prophylactic treatment. In recent
years, specific pharmaceutical treatments targeting calcitonin
gene-related peptide (CGRP) signalling molecules have provided safe and
effective treatments; monoclonal antibodies for prophylaxis and gepants
for acute therapy.
Albeit the beneficious impact of these new drugs, it is important to
understand the molecular mechanisms involved to better understand
migraine pathophysiology and improve the therapy. Here we describe
current views on the role of the CGRP family of peptides CGRP,
calcitonin (CT), adrenomedullin (AM), amylin (AMY) and their receptors
in the trigeminovascular system (TGV). All these molecules are present
within the TGV system but differ in expression and localization. It is
likely that they have different roles, which can be utilized in
providing additional drug targets.
Key words . CGRP, adrenomedullin, amylin, calcitonin, CLR,
RAMPs, receptors
INTRODUCTION
Migraine is a complex disorder, known for centuries but still not fully
understood. Affecting 1 billion people, migraine is one of the most
prevalent, disabling neurological disorders worldwide. Migraine has a
female predominance with debilitating impact in the most active years
(2018; GBD 2016 Disease and Injury Incidence and Prevalence
Collaborators, 2017). Currently, the migraine attack is proposed to
start in the central nervous system (CNS), mainly involving regions such
as hypothalamus and brainstem (Goadsby, Holland, Martins-Oliveira,
Hoffmann, Schankin & Akerman, 2017). Evidence of migraine initiating in
the CNS has been demonstrated in longitudinal neuroimaging studies over
30 days in spontaneous migraine attacks (Schulte, Mehnert & May, 2020;
Schulte, Menz, Haaker & May, 2020). The studies revealed that
hypothalamic activation during the premonitory phase of a spontaneous
migraine attack, and ictally there was activity in brainstem regions
often discussed in migraine. However, the link with the
trigeminovascular (TGV) system and the CNS is still unclear; either the
CNS is the sole activator of the trigeminal nucleus caudalis (TNC) and
subsequently the TGV system or the incoming signals from the TGV system
can be modified by brainstem nuclei. Following activation of the
1st order neurons in the TG, the sensory nerve fibres
transmit pain signals to the lower brainstem and spinal cord C1 - C3,
verified in tracing studies, and send signals to second order ascending
neurons to various CNS regions such as brainstem nuclei and thalamus
(Edvinsson, 2011).
Until 25 years ago, neurologists had few, and often insufficient,
options to treat patients with acute migraine attacks apart from general
analgesics alone or in combinations. Understanding the mechanisms of
ergotamine related molecules resulted in development of the triptan
group of acute medications; acting with high specificity on serotonin
(5-HT1B and 5-HT1D) receptors. The
triptans may act via at least 3 sites; (i) they are cranial
vasoconstrictors with possibility of cardiovascular side-effects (Saxena
& Den Boer, 1991), (ii) they inhibit neuropeptide release (Amrutkar,
Ploug, Hay-Schmidt, Porreca, Olesen & Jansen-Olesen, 2012; Goadsby &
Edvinsson, 1994), and (iii) may inhibit second-order neurons of the TGV
pain pathway (Goadsby & Knight, 1997).
Due to the high probability of cardiovascular adverse events, there was
a need for new drugs without vasoconstrictor effects. This work lead to
a new group of prophylactic agents, monoclonal antibodies (mAbs) towards
CGRP or selective binding to CGRP receptor components. These new mAbs
have since proven to be effective and have few side-effects (Edvinsson,
Haanes, Warfvinge & Krause, 2018). Currently, upcoming additions to
acute anti-migraine pharmacotherapy includes the 5-HT1Freceptor class of agonists, the ditans (Labastida-Ramirez et al., 2020),
and the CGRP receptor antagonists, the gepants (Edvinsson, Haanes,
Warfvinge & Krause, 2018).
This review provides a brief description of mechanistic actions of the
molecules acting through CGRP related mechanisms in relation to migraine
therapy, and discusses the actions based on available molecular data.
Combined, we propose ways towards improving therapy of acute and
prophylactic treatments of migraine at sites involving other members of
the CGRP family of peptides.