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