L’migraine is a chronic, debilitating neurological condition that affects women 3 to 4 times more than men. Although an estimated 1.1 billion people are affected by this condition, the physiological basis of migraine remains mysterious, but is widely studied.
Causes of Migraine
For the first time, researchers from the Department of Cell Biology and Physiology at the UNC School of Medicine have reconstructed how a small protein called calcitonin gene-related peptide (CGRP) affects the lymphatic vasculature, contributing to pain during migraine attacks. Their findings were published in Journal of Clinical Investigation.
“Our study highlights the importance of the brain’s lymphatic system in the pathophysiology of migraine pain,” said Kathleen M. Caron, Ph.D., the Frederick L. Eldridge Distinguished Professor and chair of the Department of Cell Biology and Physiology and senior author of the study. “We found that migraine pain is influenced by altered interactions with immune cells and by CGRP blocking the flow of cerebrospinal fluid from the meningeal lymphatics.”
CGRP, a small protein typically involved in pain transmission in neurons, is known to be elevated in the meninges, or layers of tissue surrounding the brain, during migraine attacks. The team found that increased CGRP levels also have a profound effect on the brain’s lymphatic vessels, a special system that facilitates the removal of cerebrospinal fluid and creates pathways for immune cells to patrol the brain’s protective covering.
To investigate exactly how CGRP affects the lymphatic system and contributes to migraine pain, the research team performed a plethora of in vitro and in vivo experiments. Nate Nelson-Maney, an MD-Ph.D. student in the Caron lab and the paper’s first author, led these experiments.
Using mice that were immune to the effects of CGRP, they first confirmed that they experienced less pain and spent more time in a brightly lit chamber than those vulnerable to CGRP. Bright light is a painful stimulus for migraineurs, and the ability to measure similar behaviors in mice validates the translational impact of the study.
Using cell culture techniques, they assessed how a specialized protein is spatially arranged between individual cells lining lymphatic vessels. The protein, called VE-Cadherin, helps hold lymphatic endothelial cells together and controls the amount of fluid, such as cerebrospinal fluid, that can squeeze between lymphatic endothelial cells and leave the vessels.
The researchers found that lymphatic endothelial cells treated with CGRP rearranged their VE-Cadherin proteins so that they lined up like a zipper on a jacket, maintaining a watertight seal. This arrangement prevents fluid from passing between the cells, reducing the permeability of these cell layers.
They validated this finding in the meningeal lymphatic tissue of mice models treated with nitroglycerin-induced migraine. When CGRP and a traceable dye were injected into the meningeal lymphatics, they observed a significant reduction in the amount of cerebrospinal fluid exiting the skull.
Future studies are needed to reveal more information about the relationships between migraine, CGRP, and meningeal lymphatics. The research team will work to understand how CSF drainage through the meningeal lymphatics contributes to migraine in humans through studies with and without the use of the newer FDA-approved CGRP-targeting drugs, such as Nurtec, Emgality, Ajovy, etc.
Although CGRP has been identified as the primary culprit in migraine-inducing changes in the lymphatic system, researchers do not fully understand the pathophysiology of migraine triggers and pain. More research is needed to understand how the meningeal lymphatic vasculature and hormone-related life stages in women, such as puberty, pregnancy, and menopause, play a role in migraine production.
“Given that lymphatic dysfunction is also highly prevalent in women, it is tempting to speculate that neurological disorders such as migraine might be governed by sex differences in meningeal lymphatic vasculature,” said Caron, who is also a member of the UNC Lineberger Comprehensive Cancer Center. “If this is true, then novel therapeutic strategies or drug targets that improve meningeal lymphatic and glymphatic flow in women would be desirable.”
Managing Migraine Effectively
Migraine is a neurological disorder. The severe pain of migraines is usually on one side of the head, but can be on both sides. Symptoms may also include nausea, vomiting, sensitivity to light and sound, difficulty speaking, or visual disturbances known as aura with flashes of light or blind spots. Attacks can last hours or days and can make it difficult to work, school, or other daily activities.
Migraine is common, especially in women. It is also hereditary. Migraine attacks can be triggered by many things, from weather to wine. Some lifestyle changes and treatment options can help you manage your migraine disease.
Overall, migraine treatment consists of preventative and acute therapy. Preventive therapy is medication that people take regularly to reduce the frequency and severity of headaches. Acute therapy is medication that people take as needed for migraine attacks.
Calcitonin gene-related peptide (CGRP)-targeted therapies are a new class of drugs. The CGRP protein is present in several body systems, including the brain and nervous system. It is involved in the transmission of pain signals, blood vessel dilation, and some inflammatory-like responses. Numerous studies have shown that CGRP plays a key role in causing the pain of migraine-related symptoms.
CGRP treatments help prevent or reduce migraine attacks by preventing CGRP from doing its job of dilating blood vessels in the brain and signaling pain in the nervous system. These therapies have led to a paradigm shift in CGRP-targeted treatment.
Evidence suggests that CGRP-targeted therapies are more tolerable, have fewer side effects, and may be as effective as or more effective than traditional first-line oral medications, including topiramate, beta-blockers such as propranolol, or amitriptyline.
Real-world studies have also shown that CGRP-targeted therapies can be effective in achieving a 50% reduction in monthly headache days, even if patients have previously tried multiple migraine preventative medications.
There are two main types of anti-CGRP drugs:
CGRP monoclonal antibodies: Used as a migraine preventative, these antibodies bind to the CGRP protein and directly neutralize it. In this way, they can reduce the frequency and severity of migraines. These drugs include erenumab, galcanezumab, fremanezumab, and eptinezumab.
For the acute treatment of headaches, you can also take another drug as needed, that is, when a migraine attack occurs.
CGRP receptor antagonists: Used primarily to treat acute migraine attacks, these medications block CGRP from binding to receptors and triggering the pain and other symptoms of a migraine. These include ubrogepant, rimegepant, atogepant, and zavegepant. However, atogepant and rimegepant can also be used to prevent migraines.
Experts say the most important thing is for patients to work with their doctor to find the right medications or other treatments for them. What works for one patient may not necessarily be appropriate for another. Some medications are not safe during pregnancy.
They also suggest discussing with a healthcare professional the risk of medication overuse headaches, which can occur when medications stop relieving pain and start causing headaches.
Non-drug measures can also help people manage migraines, including:
•Maintain healthy eating, sleeping and physical activity habits.
•Relax in a dark, quiet room.
•Apply hot or cold compresses to the neck or head.
•Try a small amount of caffeine.
•Manage stress.
#Migraine #caused #lack #drainage #lymphatic #system #brain
