Theranostics 2023; 13(8):2531-2551. doi:10.7150/thno.81332 This issue Cite
1. Centre for Discovery Brain Sciences, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
2. Center for Regenerative Therapies Dresden, TU Dresden, Fetscherstraße 105, 01307 Dresden, Germany
3. Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, 1650 Cedar Ave., Montreal, Quebec, H3G 1A4
4. Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XR, UK
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.
Keywords: chronic inflammation, histamine receptors, zebrafish, irf8, Betazole, Bortezomib, Sildenafil, Cimetidine