Highlights from

EAN 2019

European Academy of Neurology

Oslo 29 June - 2 July 2019

The role of neurogenic inflammation in migraine

In his plenary lecture, Prof Lars Edvinsson (Lund University, Sweden) discussed the evidence for a role of neuroinflammation in initiation of a migraine attack; the possibility of neurogenic inflammation caused by subsequent antidromic neuropeptide release during an attack (predominantly calcitonin gene-related peptide (CGRP); and the novel concept of neurogenic neuroinflammation in migraine chronification [1].

“It has taken me 35 years to convince the world of the important role CGRP plays in migraine”, Prof. Edvinsson said. He has always believed migraine to be a brain disease, a disorder in which CNS dysfunction plays a pivotal role: “Migraine symptoms all come from the brain.” The trigeminal ganglion (TG) plays a key role in primary headache pathophysiology, being central to the trigeminovascular reflex, which is triggered to protect against vasoconstriction. The triggering of this system leads to the perception of pain in patients with migraine. CGRP and its receptors are expressed in trigeminal neurons. In acute migraine, CGRP is released into the cranial venous outflow. Supporting the importance of CGRP is the observation that intravenous CGRP induces migraine-like symptoms in migraine patients.

Prof. Edvinsson added that recent clinical evidence does not support the notion that neuroinflammation in the dura is the cause of trigeminal activation in migraine. So, is there still a role for inflammation and/or inflammatory mediators in migraine? Yes, inflammation may play a role in chronic migraines, most notably by a mechanism termed ‘neurogenic neuroinflammation’. This mechanism possibly entails increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. Neurogenic inflammation is characterised by the release of neuropeptides, such as CGRP, from the trigeminal innervation.

CRGP has been shown to induce release of inflammatory mediators from trigeminal satellite glial cells. Blockade of this effect by anti-CGRP medication –the so-called gepants and monoclonal antibodies (mAbs)– may contribute to their anti-migraine effects. Inflammatory mediators in the TG may also contribute to sensitisation and chronification of migraine mechanisms. “Apparently, migraine drugs act outside of the blood-brain barrier (BBB)”, Prof. Edvinsson stated. He added that CGRP targets are found both in the CNS and peripherally. “The TG and dura are not protected by the BBB, which may help explain the therapeutic effect of the antibodies.” About the ability of different migraine drugs to cross the BBB, he noted the following:

  • sumatriptan does not readily cross the BBB (<3%);
  • CGRP-receptor blockers (gepants) hardly cross the BB (only 2-3%);
  • antibodies are large molecules and do not cross the BBB (<0.1%).

Prof. Edvinsson summarised CGRP-treatments as follows:

  • mAbs binding to CGRP: eptinezumab, fremanezumab, galcanezumab.
  • mAb binding to the CGRP-receptor: erenumab.
  • Small-molecule CGRP-receptor antagonists, all currently undergoing clinical trials: ubrogepant (formerly MK-1602) for acute migraine; atogepant (MK-8031) for the prevention of migraine, and rimegepant (via nasal spray) for acute attacks as well as prevention of migraine.

Key properties of mAbs as treatment options for migraine:

  • exquisite specificity (high avidity from two binding sites);
  • no liver toxicity;
  • long half-life (weeks/over one month);
  • large size (150 kDa): they must be injected and not cross the BBB.
  1. Edvinsson L. EAN 2019, PLEN03_4

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.