(ii). Relation to the blood-brain barrier.
In light of a vascular mechanisms of anti-migraine drugs, the possible
relation of CGRP or its antagonists and the effect on dilation of
cerebral arteries, must be considered. Importantly, the endothelium in
these vessels restricts passage of molecules from the vessel lumen to
the smooth muscle layers of the vascular wall containing CGRP nerve
endings. The hypothesis was tested in isolated rat middle cerebral
arteries that were cannulated and luminally perfused, enabling
application of drugs to either the endothelium exposed in the lumen or
the smooth muscle layers on the abluminal side of the artery (Edvinsson,
Nilsson & Jansen-Olesen, 2007). In these experiments, CGRP as well as
AM, AMY and CT were relaxing the artery only when applied to the
abluminal surface of the cerebral artery (Edvinsson, Nilsson &
Jansen-Olesen, 2007). Moreover, neither CGRP receptor antagonists
(olcegepant and telcagepant) nor anti-CGRP antibodies blocked
CGRP-mediated dilation when applied to the lumen; they were effective
only when applied to the abluminal side. On this basis, circulating CGRP
receptor antagonists and mAbs against CGRP and the CGRP receptor, all of
which are effective in migraine, do not seem to be able to cross the
endothelial barrier to access targets in the brain vasculature.
A neurogenic inflammation occurring in the dura has also been proposed
as trigger of migraine attacks (Pietrobon & Moskowitz, 2013). However,
numerous drugs that block the plasma protein extravasation component of
neurogenic inflammation in the dura of animals have been tested in
clinical trials but have not exhibited anti-migraine efficacy. Moreover,
CGRP does not induce neurogenic inflammation in humans or rodents but
mediates only the vasodilatory aspect of inflammation (Levy, Burstein &
Strassman, 2005; Schain, Melo-Carrillo, Stratton, Strassman & Burstein,
2019). Although the idea of neurogenic inflammation has been discussed
at length over the years the role in migraine is still not clear
(Edvinsson, Haanes & Warfvinge, 2019). Aspects for and against this
hypothesis are still being discussed (Hadjikhani et al., 2020; Khan et
al., 2019).
Considering the BBB, the question remains “where do the gepants and
mAbs act” to relieve migraine headache. Looking at the dura mater, the
cerebral circulation, the brain and the TG after administration of
tracers like Evans Blue or radioactive compounds to calculate the
permeability surface (PS product) passage showed that the dura and the
TG were freely accessible (Eftekhari, Salvatore, Johansson, Chen, Zeng
& Edvinsson, 2015; Lundblad, Haanes, Grande & Edvinsson, 2015).
Induction of neurogenic inflammation using the Freud’s Adjuvant or the
“inflammation soup” revealed activation within the TG but no
quantitative increase in PS product into the CNS. Subsequent
measurements revealed minor passage by gepants (2%) or none of the mAbs
(< 0, 01%) (Johnson, Morin, Wroblewski & Johnson, 2019).
This is in support of a more recent study by Noseda showing that
labelled fremanezumab was distributed to cranial sensory and autonomic
ganglia and to the dura mater but not to the CNS in rats with
uncompromised blood-brain barrier (Noseda et al., 2020). Since the TG
and its peripheral ramifications (TGV system) are without the protection
of the blood-brain barrier it is likely that the antimigraine site of
action of the CGRP group of anti-migraine drugs reside here. This is
also the reason why there is few CNS related side-effects.