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The glymphatic system: implications for drugs for central nervous system diseases

Abstract

In the past decade, evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown. According to the glymphatic system concept, cerebrospinal fluid flows directionally through the brain and non-selectively clears the interstitium of metabolic waste. Importantly, the glymphatic system may be modulated by particular drugs such as anaesthetics, as well as by non-pharmacological factors such as sleep, and its dysfunction has been implicated in central nervous system disorders such as Alzheimer disease. Although the glymphatic system is best described in rodents, reports using multiple neuroimaging modalities indicate that a similar transport system exists in the human brain. Here, we overview the evidence for the glymphatic system and its role in disease and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

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Fig. 1: Overview of the glymphatic system.
Fig. 2: Potential pharmacological and non-pharmacological intervention targets for the glymphatic system.
Fig. 3: Hypothesized influence of glymphatic cerebrospinal fluid flow on the delivery of therapeutics to the central nervous system through four direct drug administration routes that circumvent the blood–brain barrier endothelium.

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Acknowledgements

The authors thank P. Cumming, E. Kalso, V. Kiviniemi and P. Rauhala for their helpful feedback on the manuscript. They thank D. Xue for the submitted versions of the graphical illustrations. Funding was received from the Novo Nordisk Foundation, the Lundbeck Foundation, the Paulo Foundation, University of Helsinki research funds, The Acta Anaesthesiologica Scandinavica Foundation and European Union’s Horizon 2020 research and innovation programme (grant agreement 742112 and the Marie Sklodowska-Curie grant agreement GlymPharma No 798944).

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T.O.L. and M.N. had the original idea, and T.J.L. wrote the first draft of the manuscript. T.J.L. and T.O.L. edited the manuscript. All authors commented on and approved the final version of the manuscript.

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Correspondence to Maiken Nedergaard.

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Nature Reviews Drug Discovery thanks Per Kristian Eide, Roxana Carare and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Lohela, T.J., Lilius, T.O. & Nedergaard, M. The glymphatic system: implications for drugs for central nervous system diseases. Nat Rev Drug Discov 21, 763–779 (2022). https://doi.org/10.1038/s41573-022-00500-9

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