PUBLICATION

Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage

Authors
Crilly, S., Parry-Jones, A., Wang, X., Selley, J.N., Cook, J., Tapia, V.S., Anderson, C.S., Allan, S.M., Kasher, P.R.
ID
ZDB-PUB-220202-22
Date
2022
Source
Disease models & mechanisms   15(3): (Journal)
Registered Authors
Kasher, Paul
Keywords
ACE-inhibitors, Drug screen, Intracerebral haemorrhage, Stroke, Zebrafish
MeSH Terms
  • Animals
  • Cerebral Hemorrhage/drug therapy
  • Proteomics
  • Humans
  • Drug Evaluation, Preclinical
  • Zebrafish*
  • Neuroprotection*
  • Larva
(all 8)
PubMed
35098999 Full text @ Dis. Model. Mech.
Abstract
Despite the global health burden, treatment of spontaneous intracerebral haemorrhage (ICH) is largely supportive and translation of specific medical therapies has not been successful. Zebrafish larvae offer a unique platform for drug screening to rapidly identify neuroprotective compounds following ICH. We applied the Spectrum Library compounds to zebrafish larvae acutely after ICH to screen for decreased brain cell death and identified 150 successful drugs. Candidates were then evaluated for possible indications with other cardiovascular diseases. Six compounds were identified including two angiotensin converting enzyme inhibitors (ACE-I). Ramipril and quinapril were further assessed to confirm a significant 55% reduction in brain cell death. Proteomic analysis revealed potential mechanisms of neuroprotection. Using the INTERACT2 clinical trial dataset, we demonstrate a significant reduction in the adjusted odds of an unfavourable shift in the modified Rankin Scale at 90 days for patients receiving an ACE-I after ICH (vs. no ACE-I; odds ratio 0.80; 95% confidence interval 0.68-0.95; P=0.009). The zebrafish larval model of spontaneous ICH can be used as a reliable drug screening platform, and has identified therapeutics which may offer neuroprotection.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
m292
    Point Mutation
    mq8TgTransgenic Insertion
      w2
        Point Mutation
        1 - 3 of 3
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        Human Disease / Model
        Human Disease Fish Conditions Evidence
        cerebrovascular diseasearhgef7bm292/m292standard conditionsTAS
        1 - 1 of 1
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        Sequence Targeting Reagents
        No data available
        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        mCherryEFGmCherry
        VenusEFGVenus
        1 - 2 of 2
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        Mapping
        No data available