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

The glymphatic system is essential for clearing waste from the brain. Dysfunction in this system may contribute to migraine development. The glymphatic system operates similarly to the lymphatic system. It relies on astrocytes for removing metabolic waste. Cerebrospinal fluid, or CSF, enters peri-arterial spaces and moves into interstitial fluid. This movement occurs via aquaporin-4 channels located at astrocyte feet. Eventually, the waste is drained into cervical lymph nodes. Meningeal lymphatic vessels are critical for immune surveillance and CSF regulation. Calcitonin gene-related peptide influences pain and neuroinflammation in the nervous system. In mice with migraines, glymphatic dysfunction has been observed. This dysfunction may lead to increased levels of CGRP and inflammatory factors. Cortical spreading depression may also contribute to transient perivascular space closure. Impaired glymphatic clearance may lead to more neuroinflammation and glutamatergic signaling. Further research is necessary to identify therapeutic targets for migraine treatment. Clinical relevance: This research highlights the importance of glymphatic dysfunction in migraine, suggesting potential new treatment approaches.