The University of Southampton
University of Southampton Institutional Repository

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
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, Benjamin
c7b7f371-706b-4d59-9150-94e8f254e205
Toombs, Jamie
87de1750-c129-4ea3-b2e2-4b898ca5846b
Heslegrave, Amanda J.
f79afe6b-0ebe-4591-864b-5723f0c50b6f
More, John
6f33eae7-da70-49b6-99ad-5bf768750cd4
Okemefuna, Azubuike I.
6d830dcf-dccf-4917-a4e9-81370cbdd9d6
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Graversen, Jonas H.
bb879026-eddc-410d-8a41-ae31b0abce93
Zetterberg, Henrik
65e1750c-2467-4f02-ac28-e0e41c3a76b2
Moestrup, Søren Kragh
059d0e51-7f48-4aa5-9543-9a493b38ab5c
Bulters, Diederik
d6f9644a-a32f-45d8-b5ed-be54486ec21d
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
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, Benjamin
c7b7f371-706b-4d59-9150-94e8f254e205
Toombs, Jamie
87de1750-c129-4ea3-b2e2-4b898ca5846b
Heslegrave, Amanda J.
f79afe6b-0ebe-4591-864b-5723f0c50b6f
More, John
6f33eae7-da70-49b6-99ad-5bf768750cd4
Okemefuna, Azubuike I.
6d830dcf-dccf-4917-a4e9-81370cbdd9d6
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Graversen, Jonas H.
bb879026-eddc-410d-8a41-ae31b0abce93
Zetterberg, Henrik
65e1750c-2467-4f02-ac28-e0e41c3a76b2
Moestrup, Søren Kragh
059d0e51-7f48-4aa5-9543-9a493b38ab5c
Bulters, Diederik
d6f9644a-a32f-45d8-b5ed-be54486ec21d
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b

Garland, Patrick, Morton, Matthew J., William, Haskins, Zolnourian, Ardalan, Durnford, Andrew, Gaastra, Benjamin, 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.

Text
Garland et al 2019 postprint - Accepted Manuscript
Download (2MB)
Text
fcz053 - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)
Text
Supplementary material - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)

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 Benjamin Gaastra: ORCID iD orcid.org/0000-0002-7517-6882
ORCID for Jessica Teeling: ORCID iD orcid.org/0000-0003-4004-7391
ORCID for Diederik Bulters: ORCID iD orcid.org/0000-0001-9884-9050
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

Catalogue record

Date deposited: 10 Jan 2020 17:31
Last modified: 17 Mar 2024 05:11

Export record

Altmetrics

Contributors

Author: Patrick Garland
Author: Matthew J. Morton ORCID iD
Author: Haskins William
Author: Ardalan Zolnourian
Author: Andrew Durnford
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 ORCID iD
Author: Ian Galea ORCID iD

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×