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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)2531-2551
Seitenumfang21
FachzeitschriftTheranostics
Jahrgang13
Ausgabenummer8
PublikationsstatusVeröffentlicht - 2023
Peer-Review-StatusJa

Externe IDs

PubMed 37215570
unpaywall 10.7150/thno.81332

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Betazole, Bortezomib, Sildenafil, Cimetidine, chronic inflammation, histamine receptors, irf8, zebrafish, Zebrafish/metabolism, Spinal Cord Injuries/metabolism, Mammals, Animals, Larva, Cimetidine/pharmacology, Mice, Inflammation/drug therapy, Drug Evaluation, Preclinical, Cytokines/metabolism

Bibliotheksschlagworte