Abstract / Description of output
Abstract
Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model.
Methods: We used reduced il-1β linked green fluorescent protein (GFP) reporter
gene expression as a read-out for reduced inflammation in a screen of 1081
compounds in larval zebrafish. Hit drugs were tested in a moderate contusion model in mice for cytokine regulation, and improved tissue preservation and locomotor recovery.
Results: Three compounds robustly reduced il-1β expression in zebrafish.
Cimetidine, an over-the-counter H2 receptor antagonist, also reduced the number of pro-inflammatory neutrophils and rescued recovery after injury in a zebrafish mutant with prolonged inflammation. Cimetidine action on il-1β expression levels was abolished by somatic mutation of H2 receptor hrh2b, suggesting specific action. In mice, systemic treatment with Cimetidine led to significantly improved recovery of locomotor behavior as compared to controls, accompanied by decreased neuronal tissue loss and a shift towards a pro-regenerative profile of cytokine gene expression.
Conclusion: Our screen revealed H2 receptor signaling as a promising target for
future therapeutic interventions in spinal cord injury. This work highlights the usefulness of the zebrafish model for rapid screening of drug libraries to identify therapeutics to treat mammalian spinal cord injury.
Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model.
Methods: We used reduced il-1β linked green fluorescent protein (GFP) reporter
gene expression as a read-out for reduced inflammation in a screen of 1081
compounds in larval zebrafish. Hit drugs were tested in a moderate contusion model in mice for cytokine regulation, and improved tissue preservation and locomotor recovery.
Results: Three compounds robustly reduced il-1β expression in zebrafish.
Cimetidine, an over-the-counter H2 receptor antagonist, also reduced the number of pro-inflammatory neutrophils and rescued recovery after injury in a zebrafish mutant with prolonged inflammation. Cimetidine action on il-1β expression levels was abolished by somatic mutation of H2 receptor hrh2b, suggesting specific action. In mice, systemic treatment with Cimetidine led to significantly improved recovery of locomotor behavior as compared to controls, accompanied by decreased neuronal tissue loss and a shift towards a pro-regenerative profile of cytokine gene expression.
Conclusion: Our screen revealed H2 receptor signaling as a promising target for
future therapeutic interventions in spinal cord injury. This work highlights the usefulness of the zebrafish model for rapid screening of drug libraries to identify therapeutics to treat mammalian spinal cord injury.
Original language | English |
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Journal | Theranostics |
Early online date | 23 Apr 2023 |
DOIs | |
Publication status | E-pub ahead of print - 23 Apr 2023 |
Keywords / Materials (for Non-textual outputs)
- chronic inflammation
- histamine receptors
- zebrafish
- irf8
- Betazole
- Bortezomib
- Sildenafil
- Cimetidine
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Edinburgh Drug Discovery
Asier Unciti-Broceta (Manager), Scott Webster (Manager) & Neil Carragher (Manager)
Deanery of Molecular, Genetic and Population Health SciencesFacility/equipment: Facility