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Cited by 169Traumatic Brain Injury and Neurovascular DisturbancesCerebrospinal fluid and hydrocephalusTraumatic Brain Injury Research

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Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema

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Hussain, Rashad, Tithof, Jeffrey, Wang, Wei, Cheetham-West, Arokoruba, Song, Wei, Peng, Weiguo, Sigurdsson, Björn, Kim, Daehyun, Sun, Qian, Peng, Sisi, Plá, Virginia, Kelley, Douglas H., Hirase, Hajime, Castorena-Gonzalez, Jorge A., Weikop, Pia, Goldman, Steven A., Davis, Michael J., Nedergaard, Maiken·2023·Nature
DOI 10.1038/s41586-023-06737-7PMC PMC11216305
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Abstract

Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI)1. Noradrenaline levels are increased after TBI 2-4, and the amplitude of the increase in noradrenaline predicts both the extent of injury 5 and the likelihood of mortality 6. Glymphatic impairment is both a feature of and a contributor to brain injury 7,8, but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI.

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  • Panadrenergic inhibition with prazosin, propranolol and atipamezole blocked the locus coeruleus-induced decrease in blood albumin signal.

    “Panadrenergic inhibition (i.p. administration of the α1-adrenergic receptor antagonist prazosin, the broad β-adrenergic receptor antagonist propranolol, and the α2-adrenergic antagonist atipamezole, PPA13,14) blocked the LC-induced decrease in blood albumin signal (Figure 1H).”

    From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [13]

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Metadata

Authors
Hussain, R., Tithof, J., Wang, W., Cheetham-West, A., Song, W., Peng, W., Sigurdsson, B., Kim, D., Sun, Q., Peng, S., Plá, V., Kelley, D. H., Hirase, H., Castorena-Gonzalez, J. A., Weikop, P., Goldman, S. A., Davis, M. J., & Nedergaard, M.
Affiliations
  • University of Rochester Medicine (US)
  • University of Minnesota (US)
  • University of Copenhagen (DK)
  • University of Rochester (US)
  • University of Missouri (US)
Corresponding author
  • Hussain, Rashad
  • Nedergaard, Maiken
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-11-15
Volume
623
Issue
7989
Pages
992-1000
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06737-7
PMC
PMC11216305
OpenAlex
W4388694379
Cited by
169
References
8
Citations by year
2026: 56 · 2025: 67 · 2024: 43 · 2023: 3
FWCI
27.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • U.S. Department of Defense (W911NF1910280, W81XWH)
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • EU Joint Programme – Neurodegenerative Disease Research
  • Lundbeckfonden (R386--2021--165, R155-2016-553, R155-2016–552)
  • Novo Nordisk
  • Novo Nordisk Fonden (NNF19OC0058058, NNF13OC0004260)
  • H. Lundbeck A/S
  • National Institutes of Health (W911NF1910280, W81XWH)
  • Multidisciplinary University Research Initiative (W911NF1910280)
  • National Institute on Aging (R01AG072298)
  • National Heart, Lung, and Blood Institute (R01HL122578)
  • National Institute of Neurological Disorders and Stroke (R01NS110776, U19NS128613)
  • National Center for Complementary and Integrative Health (W911NF1910280, R01AT012312, R01AT011439)
  • Army Research Office (MURI W911NF1910280, W911NF1910280)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
Keywords
traumatic brain injury, cerebral edema, glymphatic system, lymphatic drainage, norepinephrine, central venous pressure, tau phosphorylation, secondary inflammation, glymphatic flow
MeSH terms
Brain Injuries, Traumatic, Glymphatic System, Animals, Brain Edema, Disease Models, Animal, Inflammation, Norepinephrine, Phosphorylation, Receptors, Adrenergic, tau Proteins, Adrenergic Antagonists, Lymphatic Vessels, Mice

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