Brain Prize Lecture: Prof. Jes Olesen on migraine

One of the winners of the 2021 Brain Prize, the world’s largest brain research prize, was Jes Olesen, Professor of Neurology at the University of Copenhagen and Co-director of the Danish Headache Centre in Glostrup, Denmark. The prize was handed out at the ECNP 2021 Congress, where Prof. Olesen held a lecture on genetic and molecular mechanisms of migraine. He saw many opportunities for new targets that may result in medication for migraine [1].

The Brain Prize, awarded by the Lundbeck Foundation, rewards one or more neuroscientists each year who have made a ground-breaking impact on brain research with 10 million DKK (approx. 1.3 million EUR). Along with 3 others, Prof. Olesen was awarded the prize for discovering a biological mechanism 40 years ago that triggers a migraine attack, which has ultimately resulted in powerful new treatments, such as calcitonin gene-related peptide (CGRP) inhibitors.

Prof. Olesen remarked that, in many respects, migraine resembles a psychiatric disease, with patients having normal physical and neurological examination results, absence of biomarkers in the blood, and normal neuroimaging except for advanced methodologies. Migraine's classification and diagnostic criteria use the methodology of the DSM. Migraine is clinically precisely defined and has a huge socio-economic impact. It affects 16% of the population, is the second-highest cause of disability globally, and the highest among women. Prof. Olesen pointed out that migraine is difficult to study: it occurs unpredictably and with a gradual onset, and few volunteers will actually show up.

The familial relative risk of migraine with aura is 4, and of migraine without aura 2. In twins, concordance rates are higher in monozygotic than in dizygotic twins. Heritability is around 50%. Genome-wide association study (GWAS) has identified 123 genetic variants that are significantly associated with migraine, but the relative risk of each one separately is small. The rare sub-form familial hemiplegic migraine is dominantly inherited; 3 genes have been identified with causative mutations.

Like psychiatric disorders, migraine is probably a disturbance of signalling mechanisms. A human provocation model is valid for migraine without aura. Nitric oxide (NO), CGRP, pituitary adenylate cyclase-activating peptide (PACAP), prostanoids, and potassium channel (K-channel) openers can induce migraine attacks. Prof. Olesen pointed out there are several new drug targets in the nitric oxide pathway: selective inhibitors of endothelial nitric oxide synthase or neuronal NIOS (nNOS), guanylate cyclase inhibitors, PDE 5 activators, protein-kinase inhibitors, and ion channel antagonists. CGRP antagonism is of proven value and has led to the marketing of monoclonal human antibodies against CGRP or its receptor in the past few years. They revolutionise the prophylactic treatment of migraine. A mouse model has shown no additive effect of sumatriptan and olgacepant in combination with CGRP antibodies.

Many other signalling mechanisms have not yet been explored by the pharmaceutical industry but offer “a whole catalogue of opportunities” for novel drug development, Prof. Olesen stressed. Substances that are known for their ability to provoke migraine are all vasodilators. “No substance that is not a vasodilator has ever caused a migraine attack.” He specifically mentioned ATP-sensitive potassium channel (KATP) inhibitors, cilostazol, sildenafil, GTN, CGRP, PACAP-38 (see also Figure). “KATP causes migraine in 100 percent of cases, which is very exciting.” He added: “In an as yet unpublished study, we show that knocking out in mice a particular isoform of the channel Kir6.1/SUR2B, located in vascular smooth muscle cells, makes sensitisation to migraine impossible. This may be a very important and interesting finding.”

 

Figure: Migraine-inducing substances [1]


PACAP-38, Prof Olesen explained, is a peptide signaling molecule and family of CGRP. PACAP-38 is working on a membrane receptor that causes an increase in cyclic EMP, just like CGRP. “In a mouse model we have shown that we can induce a hyposensitivity response to migraine treatment in knock-out mice that lack the CGRP receptor. They can still be sensitised by PACAP. We have high hopes for PACAP antibodies, under development by 2 companies. Maybe they work precisely in those patients who do not respond to CGRP.”

1. 
   
   1. Olesen J. Genetics and signaling mechanisms of migraine. PL.06.01, ECNP 2021 Congress, 2–5 October.

 

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Posted on 26 November, 20211 February, 2024