4.7 Article

Comparison of the safety and efficacy of fingolimod and tofacitinib in the zebrafish model of colitis

Journal

FOOD AND CHEMICAL TOXICOLOGY
Volume 170, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2022.113509

Keywords

Colitis; Janus kinase inhibitors; Efficacy; Sphingosine-1 phosphate receptor modulator; Safety; Zebrafish

Funding

  1. National Institutes for Medical Research Development (NIMAD),Tehran, Iran [988800]

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Using a zebrafish colitis model, the efficacy and toxicity of tofacitinib and fingolimod were compared. The results showed that fingolimod had better efficacy, but both drugs were toxic to adult zebrafish. Therefore, while fingolimod may be a better treatment option, its toxicity should not be overlooked.
Background: Oral targeted small molecules, including sphingosine 1 phosphate receptor (S1PR) modulators and tyrosine kinase inhibitors (TKIs), seem to revolutionize the management of inflammatory bowel disease (IBD). To select the most effective treatment, there is an unmet need to comparatively study their mechanism of action, efficacy, and toxicity in the preclinical stage and further translate it into clinical practice. Methods: Using 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced adult zebrafish colitis model, LC50 of fin-golimod and tofacitinib were determined based on the acute toxicity test to compare aquatic toxicity potential. Subsequently, the efficacy of different concentrations of tofacitinib and fingolimod was compared using flow cytometry, qPCR, and histopathology analyses. Results: TNBS significantly reduced the length of villi, and the number of goblet cells increased the level of TNF-alpha, MyD88, and NF-kappa B2, the thickness of villi and necrosis, and induced histopathological changes. All of these parameters were reversed almost dose-dependently with both medications, with the highest concentration of fingolimod being superior to other groups. Additionally, results from qPCR analysis suggested that these med-ications might suppress canonical and non-canonical NF-kappa B pathways by targeting toll-like receptors and MyD88. LC50 of tofacitinib and fingolimod was 0.9014 and 0.36 mg/L, respectively. Hence, both are in the cory 1 of the Global Harmonization System (GHS) aquatic toxicity and are toxic to adult zebrafish life. Conclusion: Given the better efficacy of fingolimod, it is worth translating the effectiveness and safety of S1PR modulators into IBD patients and comparing them with TKIs in head-to-head studies; albeit, their toxicity should not be overlooked.

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