Summary: Researchers have discovered how the protein CGRP affects the brain’s lymphatic system, contributing to migraine pain. Their study reveals that CGRP prevents cerebrospinal fluid from draining, which influences migraine attacks.
This discovery could lead to new therapeutic strategies for migraines. Further research is needed to understand gender differences in migraine prevalence.
Highlights:
- CGRP influences lymphatic vessels, preventing drainage of cerebrospinal fluid and contributing to migraine pain.
- Mouse models immunized against the effects of CGRP experienced less migraine-related pain.
- Future studies aim to explore the relationship between migraines, CGRP, and the brain’s lymphatic system.
Source: A C
Migraine is a chronic and disabling neurological disease that affects women 3 to 4 times more than men. Although approximately 1.1 billion people are affected by this disease, the physiological basis of migraine remains mysterious, but is widely studied.
For the first time, researchers in the UNC School of Medicine’s Department of Cell Biology and Physiology have discovered how a small protein called calcitonin gene-related peptide (CGRP) influences the lymphatic vascular system, contributing to pain during migraine attacks.
Their results were published in the Clinical Research Journal.
“Our study highlights the importance of the brain’s lymphatic system in the pathophysiology of migraine pain,” said Kathleen M. Caron, PhD, 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 which prevents cerebrospinal fluid from flowing out of the meningeal lymphatic vessels.”
CGRP, a small protein commonly 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 increasing CGRP levels also has 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 study exactly how CGRP influences the lymphatic system and contributes to migraine pain, the research team performed a multitude of experiments. in vitro And in vivoNate Nelson-Maney, a medical and doctoral student in the Caron lab and first author of the paper, led the experiments.
Using mouse models immune to the effects of CGRP, they first confirmed that they felt less pain and spent more time in a well-lit room compared to those vulnerable to CGRP.
Bright light is a painful stimulus for migraine sufferers, 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 that line lymphatic vessels. This protein, called VE-Cadherin, helps keep lymphatic endothelial cells stuck together and controls how much fluid, such as cerebrospinal fluid, can squeeze between lymphatic endothelial cells and leave the vessels.
The researchers found that CGRP-treated lymphatic endothelial cells rearrange their VE-Cadherin proteins so that they line up like a zipper on a jacket, helping to maintain a tight seal. This arrangement prevents fluid from passing between the cells, reducing the permeability of these cell layers.
They validated this finding in meningeal lymphatic tissue from mouse models treated with nitroglycerin-induced migraine. When CGRP and a traceable dye were injected into the meningeal lymphatic vessels, they observed a significant reduction in the amount of cerebrospinal fluid exiting the skull.
Further studies are needed to reveal more information about the relationships between migraine, CGRP and meningeal lymphatics. The research team will work to understand how drainage of cerebrospinal fluid through meningeal lymphatics contributes to migraine in humans through studies with and without the use of the latest FDA-approved CGRP-targeting drugs, such as Nurtec, Emgality, Ajovy, etc.
Although CGRP has been identified as the primary culprit in the lymphatic system changes that cause migraine, researchers do not fully understand the pathophysiology of migraine triggers and pain.
Further research is needed to understand how meningeal lymphatic vasculature and hormonally related life stages in women, such as puberty, pregnancy, and menopause, play a role in migraine production.
“Given that lymphatic dysfunction also has a high prevalence in women, it is tempting to speculate that neurological disorders like migraine might be driven by sex differences in meningeal lymphatic vasculature,” said Caron, who is also a member of the UNC Lineberger Comprehensive Cancer Center.
“If this were true, then novel therapeutic strategies or drug targets that improve meningeal lymphatic and glymphatic flow in women would be desirable.”
About this migraine and neurology research news
Author: Kendall Daniels
Source: A C
Contact: Kendall Daniels – University of North Carolina
Picture: Image credited to Neuroscience News
Original research: Free access.
“Meningeal lymphatic CGRP signaling regulates pain via cerebrospinal fluid efflux and neuroinflammation in migraine models” by Kathleen M. Caron et al. JCI
Abstract
Meningeal lymphatic CGRP signaling regulates pain via cerebrospinal fluid efflux and neuroinflammation in migraine models
Recently developed antimigraine treatments targeting calcitonin gene-related peptide (CGRP) signaling are effective, although their sites of activity remain elusive. Of note, the lymphatic vasculature is sensitive to CGRP signaling, but it is unclear whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology.
Mice with CGRP receptor-deficient lymphatic vascularization (CalcrliLEC mice) treated with nitroglycerin (NTG)-mediated chronic migraine exhibit reduced pain and light avoidance compared to NTG-treated littermate controls.
Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV immune interactions compared to cells from untreated mice.
Interestingly, the relative abundance of CD4+ T cells interacting with mucosal vascular targeting cell adhesion molecule 1 (MAdCAM1) was increased in deep cervical lymph nodes of NTG-treated control mice, but not in NTG-treated CalcrliLEC mice.
Treatment of cultured hLECs with CGRP peptide induces in vitro vascular endothelial (VE) cadherin rearrangement and reduced functional permeability.
Similarly, intra-cisterna magna injection of CGRP caused VE-cadherin rearrangement, decreased cerebrospinal fluid (CSF) uptake by MLV, and impaired CSF drainage in control mice but not in CalcrliLEC mice.
Collectively, these results reveal a previously unrecognized role of lymphatic vessels in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux.
News Source : neurosciencenews.com
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