Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema

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, Jorge A. Castorena-Gonzalez, Pia Weikop, Steven A. Goldman, Michael J. Davis and Maiken Nedergaard ()
Additional contact information
Rashad Hussain: University of Rochester
Jeffrey Tithof: University of Rochester
Wei Wang: University of Rochester
Arokoruba Cheetham-West: University of Rochester
Wei Song: University of Rochester
Weiguo Peng: University of Rochester
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
Jorge A. Castorena-Gonzalez: Tulane University
Pia Weikop: University of Copenhagen Faculty of Health and Medical Sciences
Steven A. Goldman: University of Rochester
Michael J. Davis: University of Missouri
Maiken Nedergaard: University of Rochester

Nature, 2023, vol. 623, issue 7989, 992-1000

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06737-7

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