Drug screening in zebrafish larvae reveals inflammation-related modulators of secondary damage after spinal cord injury in mice

Ana-Maria Oprişoreanu, Fari Ryan, Claire Richmond, Yuliya Dzekhtsiarova, Neil O Carragher, Thomas Becker, Samuel David, Catherina G Becker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 languageEnglish
Early online date23 Apr 2023
Publication statusE-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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