Resume: Researchers discovered how the protein CGRP affects the brain’s lymphatic system, which contributes to migraine pain. Their study reveals that CGRP prevents cerebrospinal fluid from draining, which affects migraine attacks.
This finding may lead to new therapeutic strategies for migraine. More research is needed to understand gender differences in migraine prevalence.
Key Facts:
- CGRP affects the lymphatic vessels, preventing the drainage of cerebrospinal fluid and causing migraine pain.
- Mouse models immune to the effects of CGRP experienced less migraine-related pain.
- Future studies will focus on investigating the relationship between migraine, CGRP, and the lymphatic system in the brain.
Source: UN
Migraine is a chronic and debilitating neurological disorder that affects women 3 to 4 times more often than men. Despite an estimated 1.1 billion people suffering from the condition, the physiological underpinnings of migraine remain mysterious but are extensively studied.
For the first time, researchers from the UNC School of Medicine’s Department of Cell Biology and Physiology have unraveled how a small protein, calcitonin gene-related peptide (CGRP), influences the lymphatic system and contributes to pain during migraine attacks.
Their results were published in the Journal of Clinical Research.
“Our research has highlighted the importance of the brain’s lymphatic system in the pathophysiology of migraine pain,” 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, which prevents cerebrospinal fluid from draining from the lymphatic vessels of the meninges.”
CGRP, a small protein usually involved in pain transmission in neurons, is known to be increased in the meninges, the tissue layers 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 specialized system that facilitates the drainage of cerebrospinal fluid and creates pathways for immune cells to guard the brain’s protective layer.
To investigate exactly how CGRP affects the lymphatic system and contributes to migraine pain, the team of researchers conducted a large number of experiments in vitro And in the fleshNate Nelson-Maney, an MD-PhD student in the Caron lab and first author of the paper, led these experiments.
Using mouse models that were immune to the effects of CGRP, they first confirmed that they experienced less pain and spent more time in a brightly lit room compared to mice that were vulnerable to CGRP.
Bright light is a painful stimulus for people with migraines. The fact that similar behavior could be measured in mice confirms the translational impact of the research.
Using cell culture techniques, they assessed how a specialized protein is spatially arranged between the individual cells that line lymphatic vessels. The protein, called VE-Cadherin, helps lymphatic endothelial cells stick together and controls how much fluid, such as cerebrospinal fluid, can squeeze between lymphatic endothelial cells and exit the vessels.
Researchers found that lymphatic endothelial cells treated with CGRP rearrange their VE-Cadherin proteins so that they align like a zipper on a jacket, maintaining a tight seal. This arrangement prevents fluid from flowing between cells, decreasing 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 lymphatics, they saw a significant reduction in the amount of cerebrospinal fluid exiting the skull.
Future studies are needed to reveal more information about the existing relationships between migraine, CGRP, and meningeal lymphatics. The research team will work to understand how the drainage of cerebrospinal fluid through the meningeal lymphatics contributes to migraine in humans through studies with and without the use of the latest FDA-approved CGRP-targeting medications, such as Nurtec, Emgality, Ajovy, etc.
Although CGRP has been implicated as the main culprit for migraine-inducing changes in the lymphatic system, researchers do not yet fully understand the pathophysiology of migraine triggers and pain.
More research is needed to understand the role of lymphatic vessels in the meninges and hormone-related life stages in women, such as puberty, pregnancy, and menopause, in the development of migraine.
“Given that lymphatic dysfunction also shows a strong prevalence in women, it is tempting to speculate that neurological disorders such as migraine might be determined by sexual differences in the meningeal lymphatic vascularity,” 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 news about migraine and neurological research
Author: Kendall Daniels
Source: UN
Contact: Kendall Daniels – VN
Image: The image is attributed to Neuroscience News
Original research: Open access.
“Meningeal lymphatic CGRP signaling regulates pain via cerebrospinal fluid outflow and neuroinflammation in migraine models” by Kathleen M. Caron et al. JCI
Abstract
Meningeal lymphatic CGRP signaling regulates pain via cerebrospinal fluid outflow and neuroinflammation in migraine models
Recently developed anti-migraine therapies targeting calcitonin gene-related peptide (CGRP) signaling are effective, although their sites of action remain elusive. In particular, lymphatics respond to CGRP signaling, but whether meningeal lymphatics (MLVs) contribute to the pathophysiology of migraine is unknown.
Mice with lymphatic vessels deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin (NTG)-mediated chronic migraine exhibit less pain and reduced light avoidance compared to littermate mice treated with NTG.
Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG showed increased MLV-immune interaction compared to cells from untreated mice.
Interestingly, the relative proportion of CD4+ T cells interacting with mucosal vascular addressin cell adhesion molecule 1 (MAdCAM1) was increased in the deep cervical lymph nodes of NTG-treated control mice, but not in NTG-treated CalcraliLEC mice.
Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial (VE)-cadherin rearrangement and reduced functional permeability.
Similarly, intra cisterna magna injection of CGRP caused VE-cadherin rearrangement, reduced MLV cerebrospinal fluid (CSF) uptake, and impaired CSF drainage in control mice, but not in CalcraliLEC mice.
Collectively, these findings reveal a previously unknown role for lymphatics in chronic migraine, whereby CGRP signaling stimulates interactions between MLVs and the immune system and reduces CSF efflux.