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Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema

Author

Listed:
  • Rashad Hussain

    (University of Rochester)

  • Jeffrey Tithof

    (University of Rochester
    University of Minnesota)

  • Wei Wang

    (University of Rochester)

  • Arokoruba Cheetham-West

    (University of Rochester)

  • Wei Song

    (University of Rochester)

  • Weiguo Peng

    (University of Rochester
    University of Copenhagen Faculty of Health and Medical Sciences)

  • Björn Sigurdsson

    (University of Copenhagen Faculty of Health and Medical Sciences)

  • Daehyun Kim

    (University of Minnesota)

  • Qian Sun

    (University of Rochester)

  • Sisi Peng

    (University of Rochester)

  • Virginia Plá

    (University of Rochester)

  • Douglas H. Kelley

    (University of Rochester)

  • Hajime Hirase

    (University of Rochester
    University of Copenhagen Faculty of Health and Medical Sciences)

  • Jorge A. Castorena-Gonzalez

    (Tulane University)

  • Pia Weikop

    (University of Copenhagen Faculty of Health and Medical Sciences)

  • Steven A. Goldman

    (University of Rochester
    University of Copenhagen Faculty of Health and Medical Sciences)

  • Michael J. Davis

    (University of Missouri)

  • Maiken Nedergaard

    (University of Rochester
    University of Copenhagen Faculty of Health and Medical Sciences)

Abstract

Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI)1. Noradrenaline levels are increased after TBI2–4, and the amplitude of the increase in noradrenaline predicts both the extent of injury5 and the likelihood of mortality6. Glymphatic impairment is both a feature of and a contributor to brain injury7,8, 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.

Suggested Citation

  • Rashad Hussain & Jeffrey Tithof & Wei Wang & Arokoruba Cheetham-West & Wei Song & Weiguo Peng & Björn Sigurdsson & Daehyun Kim & Qian Sun & Sisi Peng & Virginia Plá & Douglas H. Kelley & Hajime Hirase, 2023. "Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema," Nature, Nature, vol. 623(7989), pages 992-1000, November.
  • Handle: RePEc:nat:nature:v:623:y:2023:i:7989:d:10.1038_s41586-023-06737-7
    DOI: 10.1038/s41586-023-06737-7
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    Cited by:

    1. Qian Sun & Sisi Peng & Qiwu Xu & Pia Weikop & Rashad Hussain & Wei Song & Maiken Nedergaard & Fengfei Ding, 2024. "Enhancing glymphatic fluid transport by pan-adrenergic inhibition suppresses epileptogenesis in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Marcello Massimini & Maurizio Corbetta & Maria V. Sanchez-Vives & Thomas Andrillon & Gustavo Deco & Mario Rosanova & Simone Sarasso, 2024. "Sleep-like cortical dynamics during wakefulness and their network effects following brain injury," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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