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
- Drug Evaluation, Preclinical
- Humans
- Larva
- Neuroprotection*
- Proteomics
- Zebrafish*
- PubMed
- 35098999 Full text @ Dis. Model. Mech.
Citation
Crilly, S., Parry-Jones, A., Wang, X., Selley, J.N., Cook, J., Tapia, V.S., Anderson, C.S., Allan, S.M., Kasher, P.R. (2022) Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage. Disease models & mechanisms. 15(3):.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping