Beyond AQP-4: convergent glymphatic-meningeal lymphatic dysfunction underlying multifactorial migraine pathogenesis

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The glymphatic system (GS) functions as a critical pathway for waste clearance from the brain, facilitating soluble protein and metabolite drainage. Recently, GS dysfunction has emerged as a potential contributor to migraine pathophysiology. GS operates similarly to the peripheral lymphatic system, dependent on astrocytes for metabolic waste removal. The clearance process involves cerebrospinal fluid entering the peri-arterial spaces, moving into the interstitial fluid via aquaporin-4 (AQP-4) channels at astrocyte feet, and eventually being drained into the cervical lymph nodes. As a downstream effector of the glymphatic system (GS), meningeal lymphatic vessels (MLVs) play a critical role in immune surveillance and regulation of cerebrospinal fluid (CSF) efflux. Calcitonin gene-related peptide (CGRP) is primarily involved in pain transmission and neuroinflammation within the nervous system. Within MLVs, CGRP modulates CSF outflow by promoting VE-cadherin rearrangement, thereby influencing pain responses in migraine mice. GS dysfunction has been observed in mice with migraine and may associate with cortical spreading depression (CSD)-induced transient perivascular space (PVS) closure. GS dysfunction has also been observed in the nitroglycerin (NTG)-induced mice migraine model. Consequently, this dysfunction might lead to the accumulation of CGRP, reactive oxygen species, and inflammatory factors, contributing to migraine initiation. In addition, CSD, a key mechanism in migraine aura, is postulated to induce transient PVS closure, disrupting GS flow. Further, impaired GS clearance would potentiate glutamatergic signaling and trigger neuroinflammation. Furthermore, AQP-4, a key component of GS, plays a crucial role in maintaining PVS function and modulating neuroinflammation. Reduced expression and impaired polarization of AQP4 may further impair GS clearance, leading to the accumulation of pathogenic mediators. GS dysfunction might be exacerbated by CSD and neuroinflammation. Further research is warranted to elucidate the underlying mechanisms and explore potential therapeutic targets aimed at restoring GS function in patients with migraine.