Migraine affects 15% of adults worldwide, the majority of whom are women. The mechanism behind these headaches, which can be disabling in their most severe form, is still debated among scientists. A study published in NatureCommunications sheds new light.
Severe headache, nausea, vomiting, sensitivity to light or sounds, migraine is not a headache like the others. Women are twice as affected as men. When migraine is chronic, it becomes a real poison on a daily basis. Although approximately 15% of the world’s population is affected by headache, the mechanisms underlying these pains are widely misunderstood. Factors genetic were highlighted, as was the involvement of some ion channels on the neurons. Scattered clues which, to date, do not allow us to have an overall view of the birth of the pain signal which leads to migraine.
To understand the origin of migraine, an international team of researchers was not interested in neurons, but in Schwann cells. These cells surround the axons neurons to isolate and protect them. They form the sheath of myelin in the peripheral nervous system; in the brain, it is the oligodendrocytes that perform this function. Schwann cells have a receptor called CLR/RAMP1 on their surface. However, the latter is activated by a very small protein, CGRP, well known to be a mediator of pain.
The hypothesis is as follows: rather than starting from the neurons, the pain signal at the origin of the migraine would be born in the Schwann cells before being transmitted to an adjacent neuron.
Migraine doesn’t start in neurons
To test it, the scientists did experiments on mice whose Schwann cells lack the CLR/RAMP1 receptor. If we administer to these rodents of CGRP, they do not seem to develop migraine – estimated by facial tenderness – whereas this is the case in those who possess the CLR/RAMP1 receptor. The relationship between CGRP and its receptor seems to participate in the formation of migraine and more broadly in the pain signal. Because in mice whose Schwann cells do not express CLR/RAMP1, an injection of capsaicin, a molecule derived from chilli, does not induce a pain signal either.
Scientists have dissected a little more the mechanism at work here. They observed that after its activation, the receptor enters inside the cell in a structure called endosome. It is then isolated from the intracellular medium, but still emits its signal. Said signal generates the production ofnitric oxide, another pain mediator. Nitric oxide activates an adjacent neuron and the pain information goes up in the brain. Because all that is described above does not happen in the brain, but in the peripheral nervous system, at the level of the nerves.
New therapeutic targets identified
” While the role of CGRP in migraine pain is well known, our study is the first to directly link Schwann cells to migraine pain. This offers potential new approaches to migraine treatment based on our better understanding of how pain is signaled from the endosome explains Nigel Bunnett, the principal investigator of this study with his Italian colleague.
The neuropeptide CGRP is already the target of several treatments against migraines. Antibodies that prevent it from interacting with its receptor or molecules that block the receptor. The goal is to somehow prevent their interaction. Now that the mechanism is refined, scientists see the potential targets multiplying. Because preventing the CLR/RAMP1 receptor from entering the cell would also be a way to thwart migraine. Another track, directly target the receptor when it is in the endosome thanks to nanoparticles.
the National Institutes of Health (NIH) has already expressed interest in the approach using nanoparticles to continue to verify its effectiveness and safety before potential human tests.
Migraine: a new mechanism identified
Article published on December 18, 2018 by Futura with AFP-Relaxnews
Researchers from CNRS, Université Côte d’Azur and Inserm have identified a mutation in a uncomfortable which promotes migraine. The molecular mechanism that has just been highlighted could inspire new treatments against migraine.
In one joint statement published on Monday, the researchers recall that if the character hereditary migraines is already known, we did not know until now the mechanism. Migraine attacks, which affect 15% of the adult population worldwide, are linked, among other things, to the electrical hyperexcitability of sensory neurons. Their electrical activity is controlled by current-generating proteins called ion channels and in particular a “TRESK” channel, which normally has an inhibitory function on electrical activity.
Researchers have demonstrated that a genetic mutation induces its dysfunction. This channel, normally capable of inhibiting the electrical activity responsible for migraine attack, splits under the effect of the mutation of a gene into two proteins, one of which is inactive while the other, by targeting other ion channels, strongly stimulates the electrical activity of neurons, causing the migraine attack .
Prevent migraine attacks by acting on ion channels
The idea is to target these ion channels in order to reduce the electrical activity of neurons and thus prevent the onset of migraine. “This is a potential new target for drugs anti-migraine », underlines the CNRS researcher, Guillaume Sandoz, who specifies that a patent has been filed and that the first trials on rats should begin at the beginning of the year with a pharmaceutical laboratory.
Many current migraine medications are actually medications designed for other targets, such as antiepileptics or antidepressants. Other migraine treatments can, if taken too much, induce migraines (such as triptans). “Finding what regulates the mechanism of migraine and having a precise target for a possible treatment would be a real breakthrough”, he says. The translation of this discovery into a real treatment is still a long way off, but the interest of the pharmaceutical industry indicates an interesting potential. The study conducted at the Valrose Institute of Biology (CNRS/Inserm/Université Côte d’Azur) and signed by eleven researchers is published in the journal Neuron of December 17.
Discovery of the first gene that causes migraine
Article by Agnès Roux published on May 7, 2013
Migraine attacks are well known, but few cures exist. Researchers have just identified a mutated gene that would play a role in this pathology. This work opens the way to the implementation of a treatment against this disease, which can prove to be very debilitating.
The migraine is not just a simple Headache : it can have serious repercussions on daily life. Besides violent headache, it can sometimes be accompanied by nausea, vomiting, and even hypersensitivity to stimuli such as sound and light. Its victims are numerous, since it is estimated that nearly 12% of French people are affected, mostly women.
Unfortunately, there is no miracle cure, and migraine sufferers are often disabled in the event of an attack. A recent study, published in the journal Science Translational Medicine, nevertheless offers a glimmer of hope. American researchers from the University of California in San Francisco have discovered the first gene linked to this pathology.
Migraine often has a hereditary character, since 60 to 70% of those affected have a parent or grandfather who also suffers. The authors conducted a genetic study on two families with a favorable ground for migraines. Their results show that most patients have a mutation in a particular gene, coding for casein kinase 1δ (CK1δ). Children of parents with the mutated gene are also often victims of migraines.
The gene mutation Ck1δ would induce migraine
The protein kinase CK1 is a enzyme which controls many cellular functions. Using cells grown in the laboratory, scientists have been able to show that the mutation of this gene led to a decrease in the production of the CK1 protein. This result demonstrates that the mutation of the gene Ck1δ has a real biochemical impact.
Is this genetic damage a cause of the appearance of migraines? The scientists looked for the answer in mice. “It is not possible to measure headache in mice, explains Louis Ptáček, director of the study. It was therefore necessary to find another way to measure the migraine state in these animals..
Mutated mice have more headaches than others
To do this, the researchers went directly to observe the brain of mutated mice, their astrocytes specifically. These brain cells, which play a role in protecting and supporting neurons, would be involved in the onset of migraines. The results agree: the concentration in calcium from astrocytes is higher in mutated mice.
The gene Ck1δ is the first gene discovered to be linked to migraine. However, it is probably not the only one involved, and many studies will have to be undertaken to understand the overall mechanism of appearance of this pathology.
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