3. SITE OF ACTION OF CGRP AND THE CGRP RECEPTOR ACTIVE DRUGS.
CGRP antagonistic molecules have by now a 2-decade history with olcegepant and telcagepant as the first small molecules that competitively antagonize the vasodilator effect of CGRP in human arteries (Edvinsson et al., 2002). They were studied in several clinical trials, but the program was halted because of hepatotoxicity. Following molecular modifications three other gepants have now passed phase III and are approved by the FDA; these are atogepant, ubrogepant (Rubio-Beltran, Chan, Danser, MaassenVanDenBrink & Edvinsson, 2020) and rimegepant (Mulder et al., 2020). The drugs were initially designed for acute therapy, but they are now also studied for prophylaxis. The other class of molecules are humanized monoclonal antibodies directed towards different parts of the CGRP molecule per se (eptinezumab, fremanezumab, galcanezumab) or a human antibody which binds to the N-terminals of CLR and RAMP1 (erenumab). They have all passed extensive clinical studies with significant effects and minor adverse events, subsequently they are now approved for migraine prophylaxis. While these molecules are effective in prophylaxis of chronic migraine their respective sites of action remains unclear.
(i). Action on intracranial blood vessels.
Dilatation of the middle meningeal arteries and neurogenic inflammation, in the dura mater, have been suggested as a triggering mechanism regarding migraine pathophysiology. The direct activation of trigeminal afferents in the dura causes a painful headache in humans; this observation was first made in 1940 via stimulation of these vascular nerves during surgery and extended more recently to include pia mater and small pial vessels (Fontaine et al., 2018). Similarities of the occurring headache with a migraine headache led to the vascular theory of migraine, which postulates that headaches is a disorder triggered by dilation of intra- or extra-cranial blood vessels. One aspect worth considering is that nearly all vasodilators given in a peripheral vein results in “migraine-like headache or migraine” (Ashina, Hansen, BO & Olesen, 2017). However, this view is disputed since the same group of researchers did not observe that cerebral and meningeal arteries but primarily the extra-cranial arteries were dilated during a genuine migraine attack (Amin et al., 2013).
The first study of CGRP on intracranial arteries revealed very potent vasodilatation, independent of endothelial function and associated with activation of adenylyl cyclase in the vascular smooth cells (Edvinsson, Fredholm, Hamel, Jansen & Verrecchia, 1985) and with a parallel reduction in intracellular calcium ion concentration (Erdling, Sheykhzade & Edvinsson, 2017). Subsequent studies revealed that other members of the CGRP family of peptides also were vasodilators but had lower potency. While the perivascular sensory nerves had a rich supply of CGRP containing fibres, there is less expression of AMY and no ADM in nerve fibres on cerebral vessels. A subpopulation of CGRP positive TG neurons co-localized AMY, while no ADM-ir was seen (Edvinsson, Goadsby & Uddman, 2001). The receptor components CLR and RAMP1-3 were demonstrated with qPCR, suggesting that AMY receptors might occur. In agreement human cerebral pial arteries, middle cerebral, superficial temporal and middle meningeal arteries have CLR, RAMP 1, RAMP2 and RAMP3 in the smooth muscle layers (Oliver, Wainwright, Edvinsson, Pickard & Hill, 2002). The vascular endothelium contained CLR and RAMP2, but no RAMP1 or RAMP3. Functional study of cerebral arteries revealed strong vasodilator effects by CGRP and AMY (with or without endothelium) while only at very high concentration did ADM show a relaxant effect; CGRP8-37 blocked the relaxant response. Intracortical CGRP, AMY and ADM caused increased local cerebral blood flow by 42%, 32% and 15%, respectively (Edvinsson, Goadsby & Uddman, 2001). The responses to CGRP and AMY were blocked by CGRP8-37, suggesting that the vasodilatation is mediated via CGRP receptors (both mRNA for CLR and RAMP1 were seen in the MCA) (Edvinsson, Goadsby & Uddman, 2001). Studies of CT early revealed very low relaxant effect of brain vessels (Edvinsson, Ekman, Jansen, McCulloch & Uddman, 1987); recent preliminary studies have not shown CT receptor-ir in the vessel walls, while the CGRP receptor components CLR and RAMP1 are present in human cerebral and middle meningeal arteries (Edvinsson et al., 2010). While gepants showed competitive inhibition (Edvinsson et al., 2010; Rubio-Beltran, Chan, Danser, MaassenVanDenBrink & Edvinsson, 2020) the mAbs showed competitive antagonism with no depression of maximum CGRP induced relaxation in human middle meningeal and cerebral arteries (Ohlsson, Haanes, Kronvall, Xu, Snellman & Edvinsson, 2019; Ohlsson, Kronvall, Stratton & Edvinsson, 2018). The data supports a strong role for CGRP but the lack of AMY receptor component CTR, and few AM receptors are present their role is unlikely if induction of a migraine attack if vasodilatation is the key mechanism (Ashina, Hansen, BO & Olesen, 2017; Walker et al., 2015). This view is in support by others who stated that the TGV system does not require a peripheral sensory input to be activated (Goadsby & Akerman, 2012).