CSD-Induced Arterial Dilatation and Plasma Protein Extravasation Are Unaffected by Fremanezumab: Implications for CGRP's Role in Migraine with Aura

Abstract

Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underlie migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are affected. In comparison, although CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, the inability of fremanezumab to prevent them suggests that these events are not mediated by CGRP, a conclusion with important implications for our understanding of the mechanism of action of anti-CGRP-mAbs in migraine prevention.The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that there is more than one truth to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and, consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.

Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier

“…(a)-(b)), while in Frema594-treated rats, fluorescent signal was readily detected throughout the dura, including the transverse sinus, and in blood vessel walls (Figure1(c)-(d)), and occasionally in axonal fibers(Figure 1(c), middle, right). The distribution of Frema594 in the dura appeared similar 4 hours (as in Schain et al(20)) and 1 week after it was injected intravenously.…”

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

“…Recently Burstein and colleagues showed that cortical spreading depression induced dilation and plasma protein extravasation were unaffected by the anti-CGRP mAb, fremanezumab [10]. This study adds to their previous work, where they have postulated that the new anti-migraine drugs may act to prevent CGRP binding to trigeminal Aδ-fibers in the periphery [11].…”

“…Alterations in Na + or K + channels could modulate the nodal threshold of activation. The schematic also includes a hypothesis on the mode of action of the anti-migraine antibody treatments dilation and plasma protein extravasation induced by cortical spreading depression are unaffected by the anti-CGRP mAb; Fremanezumab [10]. Therefore, the most likely target of CGRP released in migraine is the Aδfibers.…”

Monoklonale Antikörper gegen CGRP oder den CGRP-Rezeptor in der Migräneprophylaxe

“…Dies kann als Argument für eine Wirkung der monoklonalen Antikörper außerhalb der Blut-Hirn-Schranke bewertet werden (was aufgrund der pharmakologischen Eigenschaften dieser Makromoleküle und experimenteller Untersuchungen [16] naheliegend erscheint) oder aber dafür, dass eine Blockade der CGRP-vermittelten Effekte die zugrunde liegenden Prozesse nicht maßgeblich beeinflusst. Eine Reihe experimenteller Beobachtungen impliziert zwar CGRP als Modulator der cortical spreading depression (CSD) vermittelten Vasodilatation [17], doch konnten Untersuchungen im Tiermodell keinen Effekt von Fremanezumab auf die CSD-induzierten vaskulären Effekte zeigen und sprechen insoweit gegen eine Rolle von CGRP hierbei [18].…”