AAN 2026 | The role of the glymphatic system in the pathophysiology of migraine

The glymphatic system has become appreciated as being important in brain functions, but most of the attention has been focused on diseases such as Alzheimer’s, where it’s known there’s a, or believed to be a buildup of toxic materials. And so the glymphatic system being like a garbage collection system, removing those toxic materials, such as amyloid beta proteins. For migraine, it has now become a focus of attention, including in my lab, asking could this function of the glymphatic system also be contributing to migraine? And specifically, we’re thinking about inflammatory compounds and diving down even deeper. My question was with CGRP. CGRP is a neuropeptide that we recognize is important in migraine. There’s now eight FDA-approved drugs that are targeting CGRP or its receptor that are effective as preventatives and for acute treatment. So could this be a collision of two worlds, the CGRP world and the glymphatic world? And that’s what Jeff Iliff and I started tackling. And with mice, we came up with some, I think, pretty good evidence that CGRP is decreasing glymphatic flow. And this is in mice, not people, but mice. But I’d emphasize that CGRP causes migraine when injected into people in the same manner as we inject CGRP into mice. So I think it’s very likely that CGRP could be causing migraine in people by decreasing glymphatic flow. That was one major take-home. That was a long answer on that.

But the second half of the story that I talked about is even more exciting. Unless you’re a CGRP person like me, I’ll think CGRP is exciting to me. But the second part of the story is we found that we could actually treat this action of CGRP by giving the mice prazosin. Prazosin is a drug that was developed way back in the 1970s, 50 years ago, for treating hypertension. It’s relatively safe. It’s still being taken by hundreds of thousands of people every year. There’s a couple million prescriptions a year in the U.S. alone for prazosin. Not so much for hypertension, but for, and this is why we started looking at it, PTSD and insomnia and nightmares following post-traumatic stress disorder. So we’re looking at migraine and post-traumatic headache in my lab. So we thought, well, prazosin, let’s use that. Because a cocktail of drugs that included prazosin was shown by Maiken Nedergaard over a decade ago to improve glymphatic flow in awake animals. So we thought maybe since prazosin could improve glymphatic flow in general, maybe it could compensate for what CGRP is doing. And indeed, we found that’s the case. So we’re super excited by this because not only we found a mechanism we think could be important for how CGRP contributes to migraine and post-traumatic headache, but also we think we found a way that you can alleviate that problem of headache caused by CGRP.

So the last thing I’ll throw in, so now we two worlds colliding, CGRP and glymphatics. I think it’s more than that. I think we have two other worlds coming in, and that’s the vascular system and the lymphatic system. So work that’s been known for, my goodness, 30 or 40 years, CGRP is the most potent vasodilator of all the peptides. So we have vasodilation by CGRP. CGRP coming in, decreasing glymphatic flow. And the third arm coming in is the lymphatic system. Kathleen Caron has shown that CGRP reduces lymphatic flow. So the central node of all these actions, vascular, glymphatic, lymphatic is CGRP. I think that the fact that CGRP is at the intersection of these three systems could explain why it’s such a good migraine target and may explain some of the biology of migraine.

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