Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema

Research output: Contribution to journal › Journal article › Research › peer-review

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Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. / 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.

In: Nature, Vol. 623, 2023, p. 992–1000.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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 2023, 'Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema', Nature, vol. 623, pp. 992–1000. https://doi.org/10.1038/s41586-023-06737-7

APA

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. (2023). Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. Nature, 623, 992–1000. https://doi.org/10.1038/s41586-023-06737-7

Vancouver

Hussain R, Tithof J, Wang W, Cheetham-West A, Song W, Peng W et al. Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. Nature. 2023;623:992–1000. https://doi.org/10.1038/s41586-023-06737-7

Author

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. / Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. In: Nature. 2023 ; Vol. 623. pp. 992–1000.

Bibtex

@article{dd0583c279a84472ae6e25934086eb97,

title = "Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema",

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.",

author = "Rashad Hussain and Jeffrey Tithof and Wei Wang and Arokoruba Cheetham-West and Wei Song and Weiguo Peng and Bj{\"o}rn Sigurdsson and Daehyun Kim and Qian Sun and Sisi Peng and Virginia Pl{\'a} and Kelley, {Douglas H.} and Hajime Hirase and Castorena-Gonzalez, {Jorge A.} and Pia Weikop and Goldman, {Steven A.} and Davis, {Michael J.} and Maiken Nedergaard",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

doi = "10.1038/s41586-023-06737-7",

language = "English",

volume = "623",

pages = "992–1000",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema

AU - Hussain, Rashad

AU - Tithof, Jeffrey

AU - Wang, Wei

AU - Cheetham-West, Arokoruba

AU - Song, Wei

AU - Peng, Weiguo

AU - Sigurdsson, Björn

AU - Kim, Daehyun

AU - Sun, Qian

AU - Peng, Sisi

AU - Plá, Virginia

AU - Kelley, Douglas H.

AU - Hirase, Hajime

AU - Castorena-Gonzalez, Jorge A.

AU - Weikop, Pia

AU - Goldman, Steven A.

AU - Davis, Michael J.

AU - Nedergaard, Maiken

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-023-06737-7

DO - 10.1038/s41586-023-06737-7

M3 - Journal article

C2 - 37968397

AN - SCOPUS:85176596380

VL - 623

SP - 992

EP - 1000

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

ID: 374129322

Center for Translational Neuromedicine