Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro model of subarachnoid haemorrhage
Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro model of subarachnoid haemorrhage
During subarachnoid haemorrhage, a blood clot forms in the subarachnoid space releasing extracellular haemoglobin (Hb), which causes oxidative damage and cell death in surrounding tissues. High rates of disability and cognitive decline in SAH survivors are attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin sequesters Hb for clearance, but this scavenging system is overwhelmed after a haemorrhage. Whilst exogenous haptoglobin application can attenuate cytotoxicity of Hb in vitro and in vivo, the functional effects of sub-lethal Hb concentrations on surviving neurons and whether cellular function can be protected with haptoglobin treatment remain unclear. Here we use cultured neurons to investigate neuronal health and function across a range of Hb concentrations to establish the thresholds for cellular damage and investigate synaptic function. Hb impairs ATP concentrations and cytoskeletal structure. At clinically relevant but sub-lethal Hb concentrations, we find that synaptic AMPAR-driven currents are reduced, accompanied by a reduction in GluA1 subunit expression. Haptoglobin co-application can prevent these deficits by scavenging free Hb to reduce it to sub-threshold concentrations and does not need to be present at stoichiometric amounts to achieve efficacy. Haptoglobin itself does not impair measures of neuronal health and function at any concentration tested. Our data highlight a role for Hb in modifying synaptic function in surviving neurons, which may link to impaired cognition or plasticity after SAH and support the development of haptoglobin as a therapy for subarachnoid haemorrhage. (Figure presented.)
excitability, haptoglobin, patch clamp, subarachnoid haemorrhage, synaptic transmission
90-103
Warming, Hannah
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Deinhardt, Katrin
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Garland, Patrick
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More, John
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Bulters, Diederik
a0586d7d-a447-464d-9ec6-fe151a22babe
Galea, Ian
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Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
October 2023
Warming, Hannah
52e41d3f-0cf4-440f-b0c9-cec47ed3b23a
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Garland, Patrick
1d24a0cc-81f2-4ef1-82bd-77d2510e59d6
More, John
6f33eae7-da70-49b6-99ad-5bf768750cd4
Bulters, Diederik
a0586d7d-a447-464d-9ec6-fe151a22babe
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Warming, Hannah, Deinhardt, Katrin, Garland, Patrick, More, John, Bulters, Diederik, Galea, Ian and Vargas-Caballero, Mariana
(2023)
Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro model of subarachnoid haemorrhage.
Journal of Neurochemistry, 167 (1), .
(doi:10.1111/jnc.15936).
Abstract
During subarachnoid haemorrhage, a blood clot forms in the subarachnoid space releasing extracellular haemoglobin (Hb), which causes oxidative damage and cell death in surrounding tissues. High rates of disability and cognitive decline in SAH survivors are attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin sequesters Hb for clearance, but this scavenging system is overwhelmed after a haemorrhage. Whilst exogenous haptoglobin application can attenuate cytotoxicity of Hb in vitro and in vivo, the functional effects of sub-lethal Hb concentrations on surviving neurons and whether cellular function can be protected with haptoglobin treatment remain unclear. Here we use cultured neurons to investigate neuronal health and function across a range of Hb concentrations to establish the thresholds for cellular damage and investigate synaptic function. Hb impairs ATP concentrations and cytoskeletal structure. At clinically relevant but sub-lethal Hb concentrations, we find that synaptic AMPAR-driven currents are reduced, accompanied by a reduction in GluA1 subunit expression. Haptoglobin co-application can prevent these deficits by scavenging free Hb to reduce it to sub-threshold concentrations and does not need to be present at stoichiometric amounts to achieve efficacy. Haptoglobin itself does not impair measures of neuronal health and function at any concentration tested. Our data highlight a role for Hb in modifying synaptic function in surviving neurons, which may link to impaired cognition or plasticity after SAH and support the development of haptoglobin as a therapy for subarachnoid haemorrhage. (Figure presented.)
Text
Journal of Neurochemistry - 2023 - Warming - Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro
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More information
Accepted/In Press date: 31 July 2023
e-pub ahead of print date: 13 September 2023
Published date: October 2023
Additional Information:
Funding Information:
This study was funded by the Gerald Kerkut Charitable Trust and Institute for Life Sciences, University of Southampton.
Publisher Copyright:
© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
Keywords:
excitability, haptoglobin, patch clamp, subarachnoid haemorrhage, synaptic transmission
Identifiers
Local EPrints ID: 485289
URI: http://eprints.soton.ac.uk/id/eprint/485289
ISSN: 0022-3042
PURE UUID: aee74d91-4349-4b1a-96d5-24032a9a020c
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Date deposited: 04 Dec 2023 17:31
Last modified: 18 Mar 2024 03:24
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Author:
John More
Author:
Diederik Bulters
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