summary: Researchers have discovered how the protein CGRP acts on the brain’s lymphatic system to affect migraines. The study revealed that CGRP blocks the drainage of cerebrospinal fluid, influencing migraine attacks.
This finding may lead to new treatment strategies for migraine. Further research is needed to understand gender differences in migraine prevalence.
Key Facts:
- CGRP affects lymphatic vessels, preventing the drainage of cerebrospinal fluid and contributing to migraine pain.
- In mouse models where CGRP is unaffected, migraine-related pain was reduced.
- Future studies aim to investigate the relationship between migraine, CGRP, and the brain’s lymphatic system.
sauce: University of North Carolina
Migraine is a chronic, debilitating neurological disorder that is three to four times more common in women than in men. Despite an estimated 1.1 billion people suffering from the condition, the physiological basis of migraine remains mysterious but is being actively researched.
Researchers in the Department of Cell Biology and Physiology at the University of North Carolina School of Medicine have now for the first time uncovered how a small protein called calcitonin gene-related peptide (CGRP) affects the lymphatic vasculature and contributes to pain during migraine attacks.
The results of their research are Clinical Research Journal.
“Our study highlights the importance of the brain’s lymphatic system in the pathophysiology of migraine,” said Kathleen M. Caron, PhD, the Frederick L. Eldridge Distinguished Professor and chair of the Department of Cell Biology and Physiology, and lead author of the study.
“We found that migraine pain is influenced by altered interactions with immune cells and by CGRP impeding the drainage of cerebrospinal fluid from meningeal lymphatic vessels.”
CGRP is a small protein normally involved in transmitting pain in neurons and is known to be increased in the meninges, the layer of tissue that surrounds the brain, during a migraine attack.
The team found that elevated CGRP levels also had a profound effect on the brain’s lymphatic vessels, a specialized system that facilitates the removal of cerebrospinal fluid and creates a pathway for immune cells to patrol the brain’s protective membrane.
To investigate how CGRP affects the lymphatic system and contributes to migraines, the research team performed a number of experiments. In vitro and In vivoNate Nelson Manney, a medical doctoral student in Caron’s lab and first author on the paper, led the experiments.
The team first used a mouse model that was unaffected by CGRP and found that it suffered less pain and spent more time in a bright room than a mouse model that was sensitive to CGRP.
Bright light is a painful stimulus for migraine sufferers, and being able to measure similar behavior in mice demonstrates the applied implications of this research.
Using cell culture techniques, the researchers assessed how a specialized protein is spatially arranged between individual cells lining the lymphatic vessels. This protein, called VE-cadherin, keeps lymphatic endothelial cells stuck together and controls how much fluid, such as cerebrospinal fluid, can squeeze through them to leave the blood vessels.
The researchers found that lymphatic endothelial cells treated with CGRP rearranged the VE-cadherin protein so that it aligned and stayed sealed like the zipper on a jacket. This arrangement prevented fluid from passing between the cells, making these cell layers less permeable.
The researchers tested their findings in meningeal lymphatic tissue from a mouse model of nitroglycerin-induced migraine: when they injected CGRP and a traceable dye into the meningeal lymphatics, they observed a significant reduction in the amount of cerebrospinal fluid draining from the skull.
Future studies are needed to shed more light on the existing relationship between migraine, CGRP, and meningeal lymphatics. Through studies with and without the use of the latest FDA-approved CGRP-targeted drugs, such as Nurtec, Emgality, and Ajovy, the research team aims to understand how cerebrospinal fluid drainage through meningeal lymphatics affects migraine in humans.
Although CGRP has been identified as the primary culprit behind the changes in the lymphatic system that lead to migraines, researchers do not fully understand migraine triggers and the pathophysiology of pain.
Further research is needed to understand the meningeal lymphatic system and how female hormone-related life stages, such as puberty, pregnancy, and menopause, affect the occurrence of migraine headaches.
“Because lymphatic dysfunction is also more prevalent in women, it is tempting to speculate that neurological disorders such as migraines may be influenced by sex-related differences in meningeal lymphatics,” said Caron, who is also a member of the University of North Carolina Lineberger Comprehensive Cancer Center.
“If this is true, new therapeutic strategies and drug targets to enhance meningeal lymphatic and glymphatic flow in women would be desirable.”
About this Migraine and Neurology Research News
author: Kendall Daniels
sauce: University of North Carolina
contact: Kendall Daniels – UNC
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Meningeal lymphatic CGRP signaling regulates pain through cerebrospinal fluid outflow and neuroinflammation in a migraine model” by Kathleen M. Caron et al. JCI
Abstract
Meningeal lymphatic CGRP signaling regulates pain through cerebrospinal fluid outflow and neuroinflammation in a migraine model
Recently developed migraine drugs targeting calcitonin gene-related peptide (CGRP) signaling are effective but their site of action remains unclear. In particular, lymphatic vessels respond to CGRP signaling, but it is unclear whether meningeal lymphatic vessels (MLVs) are involved in migraine pathophysiology.
Mice with lymphatic vessels defective in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin (NTG) for chronic migraine headaches exhibit reduced pain and light avoidance compared with NTG-treated littermate controls.
Gene expression profiling of lymphatic endothelial cells (LECs) isolated from the meninges of NTG-treated Rpl22HA/+;Lyve1Cre RiboTag mice revealed increased MLV immune interactions compared with cells from untreated mice.
Interestingly, the relative abundance of CD4+ T cells interacting with the mucosal vascular addressin cell adhesion molecule 1 (MAdCAM1) was increased in the deep cervical lymph nodes of NTG-treated control mice but not NTG-treated CalcrliLEC mice.
Treatment of cultured hLECs with CGRP peptide in vitro induced rearrangement of vascular endothelial (VE)-cadherin and reduced functional permeability.
Similarly, intracisternal injection of CGRP caused VE-cadherin relocation, reduced cerebrospinal fluid (CSF) uptake by MLVs, and inhibited CSF drainage in control but not CalcrliLEC mice.
Together, these findings reveal a previously unrecognized role for lymphatics in chronic migraine and demonstrate that CGRP signaling promotes MLV-immune interactions and reduces CSF outflow.
