Etiology of intracerebral hemorrhage (ICH): novel insights from Zebrafish embryos

Eisa-Beygi, Shahram; Rezaei, Mohammad

doi:10.1387/ijdb.160136se

Cited by 12 publications

(6 citation statements)

References 87 publications

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“…1 A). Because intracerebral hemorrhage is induced in zebrafish by a variety of gene mutations and morpholino-mediated gene knockdown, as well as after treatment with various compounds ( Eisa-Beygi and Rezaei, 2016 ), we were unable to determine the cause of intracerebral hemorrhage at this stage. Instead, based on this lethal phenotype we came up with the strategy of developing in vivo assay for IRE1α inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Development of a Rapid <i>in vivo</i> Assay to Evaluate the Efficacy of IRE1-specific Inhibitors of the Unfolded Protein Response Using Medaka Fish

Jin

Ishikawa

Taniguchi

et al. 2019

Cell Struct. Funct.

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Three types of transmembrane protein, IRE1/IRE1, PERK, and ATF6/ATF6 are expressed ubiquitously in vertebrates as transducers of the unfolded protein response (UPR), which maintains the homeostasis of the endoplasmic reticulum. IRE1 is highly conserved from yeast to mammals, and transmits a signal by a unique mechanism, namely splicing of mRNA encoding XBP1, the transcription factor downstream of IRE1 in metazoans. IRE1 contains a ribonuclease domain in its cytoplasmic region which initiates splicing reaction by direct cleavage of XBP1 mRNA at the two stem loop structures. As the UPR is considered to be involved in the development and progression of various diseases, as well as in the survival and growth of tumor cells, UPR inhibitors have been sought. To date, IRE1 inhibitors have been screened using cell-based reporter assays and fluorescent-based in vitro cleavage assays. Here, we used medaka fish to develop an in vivo assay for IRE1 inhibitors. IRE1, IRE1, ATF6 and ATF6 are ubiquitously expressed in medaka. We found that IRE1/ATF6-double knockout is lethal, similarly to IRE1/IRE1-and ATF6/ATF6-double knockout. Therefore, IRE1 inhibitors are expected to confer lethality to ATF6-knockout medaka but not to wild-type medaka. One compound named K114 was obtained from 1,280 compounds using this phenotypic screening. K114 inhibited ER stress-induced splicing of XBP1 mRNA as well as reporter luciferase expression in HCT116 cells derived from human colorectal carcinoma, and inhibited ribonuclease activity of human IRE1 in vitro. Thus, this phenotypic assay can be used as a quick test for the efficacy of IRE1 inhibitors in vivo.

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Section: Resultsmentioning

confidence: 99%

Development of a Rapid <i>in vivo</i> Assay to Evaluate the Efficacy of IRE1-specific Inhibitors of the Unfolded Protein Response Using Medaka Fish

Jin

Ishikawa

Taniguchi

et al. 2019

Cell Struct. Funct.

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“…93 Nevertheless, one of the mammalian studies also revealed the chronic blood-brain barrier disruption and neuroinflammation as part of the impact after the TBI. 94 Intracerebral hemorrhage in larval zebrafish can show spontaneous brain-specific bleeding without any invasive techniques 95,96 and yet still able to better mimic this aspect of the human TBI condition compared to the commonly used rodent models. 97,98 In brief, atorvastatin (ATV), a known substance to cause spontaneous cerebral-specific blood vessel rupture, was solubilized for zebrafish larvae/embryo treatment in an embryo medium-filled petri dish ( Figure 4G) and those exhibiting ICH at 24 h were separated for further analysis.…”

Section: Larval Intracerebral Hemorrhage (Ich) Modelmentioning

confidence: 99%

“…97,98 In brief, atorvastatin (ATV), a known substance to cause spontaneous cerebral-specific blood vessel rupture, was solubilized for zebrafish larvae/embryo treatment in an embryo medium-filled petri dish ( Figure 4G) and those exhibiting ICH at 24 h were separated for further analysis. 95,[99][100][101] Some studies alternately used the "bubblehead" (bbh) mutant zebrafish line which can exhibit spontaneous ICH similar to ATV. 96 Comparison between the two ICH protocols is yet to be discussed, but both manage to achieve similar ICH injuries in the zebrafish larval model.…”

Section: Larval Intracerebral Hemorrhage (Ich) Modelmentioning

confidence: 99%

The utilization of small non‐mammals in traumatic brain injury research: A systematic review

et al. 2021

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Traumatic brain injury (TBI) is one of the leading causes of death and morbidity worldwide especially in industrialized countries. 1 TBI has become a major public health concern with a global prevalence that has escalated to almost 27.08 million people in 2016 as reported by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study. 2 The study also stated that about 8.1 million people were living with long-term disability caused by TBI, mainly due to falls and motor vehicle accidents. Traumatic brain injury has also been alarmingly related to a number of adverse long-term effects, including elevated risk toward long-term complications such as Parkinson's disease, Alzheimer's disease, Dementia Pugilistica, and posttraumatic epilepsy. 3 TBI is comprised of two phases which are the primary and secondary injury phase. The primary injury phase is the initial impact encountered from the external mechanical force that results in blood vessel damage, axonal tearing, 4 cell death at the injury site, blood-brain barrier disruption, presence of edema, and generation of damage-associated molecular patterns (DAMPs). 5

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“…Comparably, the ‘bubblehead’ (bbh) mutant line, which expresses a hypomorphic mutation in the arhgef7 gene, encoding the Rac GEF βpix, also exhibit spontaneous ICH and hydrocephalus within a similar time frame to the ATV model ( Liu et al , 2007 ; ten Klooster et al , 2006 ). ICH is induced through comparable mechanistic defects in both ATV and bbh models ( Eisa-Beygi & Rezaei, 2016 ) ( Supplementary Figure 1 ). Although several groups have utilised these models to study the development and integrity of the cerebrovasculature ( Buchner et al , 2007 ; Huang et al , 2018 ; Li et al , 2017 ; Liu et al , 2007 ; Yang et al , 2017 ), they have not yet been used to study the pathological and neuroinflammatory consequences of bleeding in the zebrafish larval brain in the context of human ICH.…”

Section: Introductionmentioning

confidence: 96%

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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Etiology of intracerebral hemorrhage (ICH): novel insights from Zebrafish embryos

Cited by 12 publications

References 87 publications

Development of a Rapid <i>in vivo</i> Assay to Evaluate the Efficacy of IRE1-specific Inhibitors of the Unfolded Protein Response Using Medaka Fish

Development of a Rapid <i>in vivo</i> Assay to Evaluate the Efficacy of IRE1-specific Inhibitors of the Unfolded Protein Response Using Medaka Fish

The utilization of small non‐mammals in traumatic brain injury research: A systematic review

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

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