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Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema.

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 DH
Hirase H
Castorena-Gonzalez JA
Weikop P
Goldman SA
Davis MJ
Nedergaard M
Source :
Nature [Nature] 2023 Nov; Vol. 623 (7989), pp. 992-1000. Date of Electronic Publication: 2023 Nov 15.
Publication Year :
2023

Abstract

Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI) <superscript>1</superscript> . Noradrenaline levels are increased after TBI <superscript>2-4</superscript> , and the amplitude of the increase in noradrenaline predicts both the extent of injury <superscript>5</superscript> and the likelihood of mortality <superscript>6</superscript> . Glymphatic impairment is both a feature of and a contributor to brain injury <superscript>7,8</superscript> , 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.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Details

Language :
English
ISSN :
1476-4687
Volume :
623
Issue :
7989
Database :
MEDLINE
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
37968397
Full Text :
https://doi.org/10.1038/s41586-023-06737-7