Basic and Translational Research in Intracerebral Hemorrhage

Selim, Magdy; Hanley, Daniel F.; Broderick, Joseph P.; Goldstein, Joshua N.; Gregson, Barbara; Falcione, Guido; Gonzales, Nicole R.; Gurol, M. Edip; Kersten, Jocelyn; Lewkowicz, Henry; Mendelow, AD; Muehlschlegel, Susanne; Neuman, Richey; Yu, Amy Y.X.; Rosenblum, Michael; Sheth, Kevin N; Singh, Vineeta; Ziai, Wendy; Keep, Richard F.; Aronowski, Jaroslaw; Genstler, Curtis; James, Michael L.; Ratan, Rajiv R.; Sansing, Lauren H; Youd, Anna; Xi, Guohua; Zille, Marietta; Anderson, Craig; Awad, Issam A.; Bastings, E.; Bednar, Martin M.; Coon, Alexander L.; Gottesman, Rebecca; Katz, Bryan; Khan, Saima; Koenig, James I.; Koroshetz, Walter J.; Ling, Shari M.; Loftus, Christopher M.; Lockhardt, John; Louis, Thomas A.; Marler, John; Moy, Claudia S.; Peña, Carlos; Pollack, Charles V.; Omert, Laurel; Shah, Monica; Shoamanesh, Ashkan; Singer, Michael S.; Steiner, Thorsten; Torbey, Michel T.; Tymianski, Mike; Wakhloo, Ajay K.; Vespa, Paul; Zuccarello, Mario; Zheng, Xiaolin

doi:10.1161/strokeaha.117.019539

Cited by 44 publications

(25 citation statements)

References 34 publications

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“…Ultimately, choice of model depends on the research question being asked. However, the translational relevance of these models has been called into question, thus reiterating the need to develop less invasive and more spontaneous techniques, or coupling these models with other experimental methods in an attempt to more closely recapitulate human ICH [ 20 ].…”

Section: Small Mammalian Modelsmentioning

confidence: 99%

“…CAA is a large risk factor for ICH patients above 70 years old; therefore, to mimic the clinical scenario, older animals are utilised in these studies. [ 14 , 20 ].Winkler et al were the first group to show that mutations in APP23 mice overexpressing APP 751 with the Swedish double mutation (K670N/M671L) under the control of a neuron-specific-Thy-1 promoter, exhibited evidence of brain haemorrhage in 27-month old mice [ 72 ]. The haemorrhage sites correlated with the CAA vessels, providing rationale for CAA being the driving force behind vessel rupture and bleeds in these transgenic mice.…”

Section: Small Mammalian Modelsmentioning

confidence: 99%

“…It would seem, therefore, that a breakdown in the current ‘drug development pipeline’ exists for ICH. As such, there is an urgent requirement to rethink our strategies for translational ICH research so that we can investigate new therapeutic avenues for future patient treatments, as highlighted in the Haemorrhagic Stroke Academia Industry (HEADS) initiative [ 20 ].This review reinforces some of the priorities raised by HEADS, and how these may be implemented within preclinical ICH research, with our main focus highlighting the need for a more efficient, multi-directional pipeline. A more strategic approach to ensure the most appropriate models/systems are selected for each phase of the pre-clinical pipeline (such as studying the occurrence of bleed/risk factors, injury responses or treatments) would be beneficial (Fig.…”

Section: Introductionmentioning

confidence: 99%

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A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

Withers

Parry‐Jones

Allan

et al. 2020

Transl. Stroke Res.

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Apart from acute and chronic blood pressure lowering, we have no specific medications to prevent intracerebral haemorrhage (ICH) or improve outcomes once bleeding has occurred. One reason for this may be related to particular limitations associated with the current pre-clinical models of ICH, leading to a failure to translate into the clinic. It would seem that a breakdown in the ‘drug development pipeline’ currently exists for translational ICH research which needs to be urgently addressed. Here, we review the most commonly used pre-clinical models of ICH and discuss their advantages and disadvantages in the context of translational studies. We propose that to increase our chances of successfully identifying new therapeutics for ICH, a bi-directional, 2- or 3-pronged approach using more than one model species/system could be useful for confirming key pre-clinical observations. Furthermore, we highlight that post-mortem/ex-vivo ICH patient material is a precious and underused resource which could play an essential role in the verification of experimental results prior to consideration for further clinical investigation. Embracing multidisciplinary collaboration between pre-clinical and clinical ICH research groups will be essential to ensure the success of this type of approach in the future.

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Section: Small Mammalian Modelsmentioning

confidence: 99%

Section: Small Mammalian Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

Withers

Parry‐Jones

Allan

et al. 2020

Transl. Stroke Res.

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show abstract

“…Unfortunately, this research has not yet resulted in the translation of any specific drugs to the clinic ( Kellner & Connolly, 2010 ; Kirkman et al ., 2011 ). Potential reasons for this include difficulties in observing cellular responses in ‘real-time’ within whole brains of intact live animals, and the invasive and artificial procedures required to induce cerebral haematomas ( MacLellan et al ., 2010 ; Selim et al ., 2018 ). Mammalian models of spontaneous ICH models do exist, such as cerebral amyloid angiopathy co-morbidity studies and use of hypertensive mice, but their usefulness is limited due to variability in haematoma size, timing and location ( Alharbi et al ., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, spontaneous brain-specific bleeding can be observed in zebrafish larvae using non-invasive techniques ( Eisa-Beygi et al ., 2013 ; Liu et al ., 2007 ), thereby eliminating specific constraints associated with mammalian models. As such, the use of larval zebrafish models of ICH could offer critical insight into the immediate cellular responses after a bleed to support the rodent community and provide a potential platform for future drug discovery addressing pre-clinical ICH priorities ( Selim et al ., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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

Crilly¹,

Njegic²,

Laurie³

et al. 2018

F1000Res

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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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Regenerative Potential of Hydrogels for Intracerebral Hemorrhage: Lessons from Ischemic Stroke and Traumatic Brain Injury Research

Thomas

Louca

Bolan

et al. 2021

Adv Healthcare Materials

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Intracerebral hemorrhage (ICH) is a deadly and debilitating type of stroke, caused by the rupture of cerebral blood vessels. To date, there are no restorative interventions approved for use in ICH patients, highlighting a critical unmet need. ICH shares some pathological features with other acute brain injuries such as ischemic stroke (IS) and traumatic brain injury (TBI), including the loss of brain tissue, disruption of the blood–brain barrier, and activation of a potent inflammatory response. New biomaterials such as hydrogels have been recently investigated for their therapeutic benefit in both experimental IS and TBI, owing to their provision of architectural support for damaged brain tissue and ability to deliver cellular and molecular therapies. Conversely, research on the use of hydrogels for ICH therapy is still in its infancy, with very few published reports investigating their therapeutic potential. Here, the published use of hydrogels in experimental ICH is commented upon and how approaches reported in the IS and TBI fields may be applied to ICH research to inform the design of future therapies is described. Unique aspects of ICH that are distinct from IS and TBI that should be considered when translating biomaterial‐based therapies between disease models are also highlighted.

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Basic and Translational Research in Intracerebral Hemorrhage

Cited by 44 publications

References 34 publications

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

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

Regenerative Potential of Hydrogels for Intracerebral Hemorrhage: Lessons from Ischemic Stroke and Traumatic Brain Injury Research

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