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Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin

Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin
Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm.

2632-1297
Garland, Patrick
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Morton, Matthew J.
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William, Haskins
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Zolnourian, Ardalan
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Durnford, Andrew
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Gaastra, Ben
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Toombs, Jamie
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Heslegrave, Amanda J.
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More, John
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Okemefuna, Azubuike I.
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Teeling, Jessica
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Graversen, Jonas H.
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Zetterberg, Henrik
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Moestrup, Søren Kragh
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Bulters, Diederik
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Galea, Ian
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Garland, Patrick
1d24a0cc-81f2-4ef1-82bd-77d2510e59d6
Morton, Matthew J.
4a178059-af3c-4de6-9d69-4024ea6178dc
William, Haskins
3f1e4539-f8b7-4128-8dff-de3063e3b417
Zolnourian, Ardalan
5e8d4881-cdfd-4cb1-8eae-b98b13104648
Durnford, Andrew
5b49b848-cf34-4024-9399-c342d71b09b6
Gaastra, Ben
c6a69fe5-84a6-4a41-990c-8999afb00822
Toombs, Jamie
87de1750-c129-4ea3-b2e2-4b898ca5846b
Heslegrave, Amanda J.
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More, John
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Okemefuna, Azubuike I.
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Teeling, Jessica
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Graversen, Jonas H.
bb879026-eddc-410d-8a41-ae31b0abce93
Zetterberg, Henrik
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Moestrup, Søren Kragh
059d0e51-7f48-4aa5-9543-9a493b38ab5c
Bulters, Diederik
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Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b

Garland, Patrick, Morton, Matthew J., William, Haskins, Zolnourian, Ardalan, Durnford, Andrew, Gaastra, Ben, Toombs, Jamie, Heslegrave, Amanda J., More, John, Okemefuna, Azubuike I., Teeling, Jessica, Graversen, Jonas H., Zetterberg, Henrik, Moestrup, Søren Kragh, Bulters, Diederik and Galea, Ian (2020) Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin. Brain Communications, 2 (1), [fcz053]. (doi:10.1093/braincomms/fcz053).

Record type: Article

Abstract

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm.

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Garland et al 2019 postprint - Accepted Manuscript
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More information

Accepted/In Press date: 16 December 2019
e-pub ahead of print date: 3 January 2020
Published date: 3 January 2020

Identifiers

Local EPrints ID: 436821
URI: http://eprints.soton.ac.uk/id/eprint/436821
ISSN: 2632-1297
PURE UUID: d2cc5c96-89fd-48ca-b057-a8f62e2c59ca
ORCID for Matthew J. Morton: ORCID iD orcid.org/0000-0003-1986-0863
ORCID for Jessica Teeling: ORCID iD orcid.org/0000-0003-4004-7391
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

Catalogue record

Date deposited: 10 Jan 2020 17:31
Last modified: 13 Nov 2021 05:28

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Contributors

Author: Patrick Garland
Author: Matthew J. Morton ORCID iD
Author: Haskins William
Author: Ardalan Zolnourian
Author: Andrew Durnford
Author: Ben Gaastra
Author: Jamie Toombs
Author: Amanda J. Heslegrave
Author: John More
Author: Azubuike I. Okemefuna
Author: Jessica Teeling ORCID iD
Author: Jonas H. Graversen
Author: Henrik Zetterberg
Author: Søren Kragh Moestrup
Author: Diederik Bulters
Author: Ian Galea ORCID iD

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