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Beyond AQP-4: convergent glymphatic-meningeal lymphatic dysfunction underlying multifactorial migraine pathogenesis
Meng-Fan Yang1,2, Mao-Mei Song2, Ying-Jie Gao2
1Department of Neurology, Headache Center, Shenzhen Baoan People's Hospital, The Second Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China.
Frontiers in Immunology
|July 11, 2026
Summary
Glymphatic system (GS) dysfunction may contribute to migraines by impairing brain waste clearance and increasing CGRP. Restoring GS function could be a therapeutic target for migraine relief.
Area of Science:
- Neuroscience
- Physiology
- Pathology
Background:
- The glymphatic system (GS) clears waste from the brain, involving cerebrospinal fluid (CSF) drainage via aquaporin-4 (AQP-4) channels and meningeal lymphatic vessels (MLVs).
- Dysfunction of the GS and MLVs is increasingly implicated in migraine pathophysiology.
- Calcitonin gene-related peptide (CGRP) plays a role in pain and neuroinflammation, and its levels are influenced by MLVs.
Purpose of the Study:
- To explore the role of glymphatic system dysfunction in migraine.
- To investigate the link between GS dysfunction, CGRP accumulation, and migraine mechanisms like cortical spreading depression (CSD).
- To highlight potential therapeutic strategies targeting the GS for migraine treatment.
Main Methods:
- Review of existing literature on glymphatic system function, migraine pathophysiology, CGRP, and AQP-4.
- Analysis of observations in animal models of migraine (e.g., NTG-induced, CSD).
- Examination of the interplay between GS, MLVs, CGRP, and neuroinflammation.
Main Results:
- GS dysfunction, potentially caused by CSD-induced perivascular space (PVS) closure, is observed in migraine models.
- Impaired GS clearance may lead to the accumulation of CGRP, reactive oxygen species, and inflammatory factors, contributing to migraine.
- Reduced AQP-4 expression or polarization further compromises GS function and neuroinflammation regulation.
Conclusions:
- Glymphatic system dysfunction is a significant factor in migraine pathophysiology.
- Targeting GS restoration and managing CGRP accumulation presents a promising therapeutic avenue for migraine.
- Further research is needed to fully elucidate GS mechanisms in migraine and develop effective treatments.
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