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Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage

Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent mo...

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Autores principales: Crilly, Siobhan, Njegic, Alexandra, Laurie, Sarah E., Fotiou, Elisavet, Hudson, Georgina, Barrington, Jack, Webb, Kirsty, Young, Helen L., Badrock, Andrew P., Hurlstone, Adam, Rivers-Auty, Jack, Parry-Jones, Adrian R., Allan, Stuart M., Kasher, Paul R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: F1000 Research Limited 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234746/
https://www.ncbi.nlm.nih.gov/pubmed/30473780
http://dx.doi.org/10.12688/f1000research.16473.2
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author Crilly, Siobhan
Njegic, Alexandra
Laurie, Sarah E.
Fotiou, Elisavet
Hudson, Georgina
Barrington, Jack
Webb, Kirsty
Young, Helen L.
Badrock, Andrew P.
Hurlstone, Adam
Rivers-Auty, Jack
Parry-Jones, Adrian R.
Allan, Stuart M.
Kasher, Paul R.
author_facet Crilly, Siobhan
Njegic, Alexandra
Laurie, Sarah E.
Fotiou, Elisavet
Hudson, Georgina
Barrington, Jack
Webb, Kirsty
Young, Helen L.
Badrock, Andrew P.
Hurlstone, Adam
Rivers-Auty, Jack
Parry-Jones, Adrian R.
Allan, Stuart M.
Kasher, Paul R.
author_sort Crilly, Siobhan
collection PubMed
description Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology.
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spelling pubmed-62347462018-11-23 Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage Crilly, Siobhan Njegic, Alexandra Laurie, Sarah E. Fotiou, Elisavet Hudson, Georgina Barrington, Jack Webb, Kirsty Young, Helen L. Badrock, Andrew P. Hurlstone, Adam Rivers-Auty, Jack Parry-Jones, Adrian R. Allan, Stuart M. Kasher, Paul R. F1000Res Method Article Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology. F1000 Research Limited 2018-11-08 /pmc/articles/PMC6234746/ /pubmed/30473780 http://dx.doi.org/10.12688/f1000research.16473.2 Text en Copyright: © 2018 Crilly S et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Method Article
Crilly, Siobhan
Njegic, Alexandra
Laurie, Sarah E.
Fotiou, Elisavet
Hudson, Georgina
Barrington, Jack
Webb, Kirsty
Young, Helen L.
Badrock, Andrew P.
Hurlstone, Adam
Rivers-Auty, Jack
Parry-Jones, Adrian R.
Allan, Stuart M.
Kasher, Paul R.
Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
title Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
title_full Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
title_fullStr Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
title_full_unstemmed Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
title_short Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
title_sort using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage
topic Method Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234746/
https://www.ncbi.nlm.nih.gov/pubmed/30473780
http://dx.doi.org/10.12688/f1000research.16473.2
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