Glymphatic and Meningeal Lymphatic Dysfunction Converge in Multifactorial Migraine Pathogenesis

The glymphatic system (GS) is crucial for brain waste clearance, removing soluble proteins and metabolites. Its dysfunction is increasingly linked to migraine pathophysiology. Operating like a peripheral lymphatic system, the GS relies on astrocytes and aquaporin-4 (AQP-4) channels to facilitate cerebrospinal fluid (CSF) movement into interstitial fluid and subsequent drainage. Downstream, meningeal lymphatic vessels (MLVs) are vital for immune surveillance and CSF efflux. Current understanding of migraine often focuses on neuroinflammation and pain transmission, but the role of impaired waste clearance and its interplay with key mediators like calcitonin gene-related peptide (CGRP) presents a significant gap in fully elucidating the disease's complex etiology.

This review synthesized existing literature to examine the convergent roles of glymphatic and meningeal lymphatic dysfunction in the multifactorial pathogenesis of migraine. The authors explored how impaired waste clearance pathways, specifically the glymphatic system and meningeal lymphatic vessels, contribute to migraine initiation and progression. They focused on the interplay between these systems and key mediators such as CGRP, AQP-4, and phenomena like cortical spreading depression (CSD), analyzing their impact on CSF dynamics, neuroinflammation, and pain responses in migraine models.

The review elucidated that GS dysfunction is a significant contributor to migraine pathophysiology, observed in both migraine and nitroglycerin (NTG)-induced migraine mouse models. This dysfunction is associated with cortical spreading depression (CSD)-induced transient perivascular space (PVS) closure, which disrupts GS flow. Impaired GS clearance leads to the accumulation of CGRP, reactive oxygen species, and inflammatory factors, all contributing to migraine initiation. Furthermore, CGRP modulates CSF outflow within MLVs by promoting VE-cadherin rearrangement, thereby influencing pain responses in migraine mice. AQP-4, a critical component of GS, maintains PVS function and modulates neuroinflammation; reduced expression and impaired polarization of AQP-4 further compromise GS clearance. This impaired clearance potentiates glutamatergic signaling and triggers neuroinflammation.

GS dysfunction, exacerbated by CSD and neuroinflammation, leads to the accumulation of CGRP, reactive oxygen species, and inflammatory factors, driving migraine pathogenesis.