Repeated dose of meloxicam induces genotoxicity and histopathological changes in cardiac tissue of mice

Abstract

Meloxicam is the non-steroidal anti-inflammatory drug most used in small animals; however, studies on genotoxicity, oxidative stress, and histopathologic alterations in cardiac tissue are limited, especially at therapeutical doses used in these animals. This study evaluated the toxic effects caused by the treatment involving repeated low at higher doses of meloxicam in mice, by genotoxicity, oxidative stress, and histopathological parameters. Mice (CF1, male) received, by gavage, meloxicam at the therapeutic dose indicated for small animals (0.1 mg/kg) and at higher doses (0.5 and 1 mg/kg) for 28 days. Later, they were euthanized for blood and organ analysis. Oxidative stress was analyzed by the plasma ferric reduction capacity (FRAP) and catalase, and genotoxicity, by the comet assay and the micronucleus test. Heart, liver, lung, and kidney tissues were analyzed by the histology, and stomach and duodenum were analyzed with a magnifying glass. The relative weight of organs did not present significant alterations. However, congestion of duodenum vessels was observed at the three tested doses and caused hyperemia of stomach mucosa at 1 mg/kg. In the heart histology there was a reduction in the number of cardiomyocytes, accompanied by an increase in cell diameter (possible cell hypertrophy) dose-dependent. The highest tested dose of meloxicam also increased the DNA damage index, without alterations in the micronucleus test. Meloxicam did not affect the catalase activity but increased the FRAP (1 mg/kg). Meloxicam at the dose prescribed for small animals could potentially cause cardiac histopathologic alterations and genotoxic effects.

Graphical Abstract

Keywords:

• Meloxicam
• repeated dose toxicity
• genotoxicity
• oxidative stress
• cardiomyocytes

Acknowledgements

The authors are grateful to Feevale University for financial support, and CNPq and CAPES for students’ fellowships. This article was originated from two Conference abstracts presented as posters in an International Congress of Toxicology , the II Latin American Congress of Clinical and Laboratory Toxicology (Toxilatin), that took place in Porto Alegre, Brazil, in June 2018. In the first abstract, the results of animals’ weight control, genotoxicity and cardiac tissue damages, such as cardiomyocytes number and their diameter, were presented:

Bigolin C; da Silva JCG, Dallegrave E, Raasch JR, Neumann TMSO, Rodrigues GZP, Staudt LBM, Moraes MF, Farias DG, Schiling G, Gehlen G, Perassolo MS, da Silva LB, Betti AH. High dose of meloxicam induces genotoxicity and alterations in the cardiac tissue after 28 days treatment in mice. Section General Toxicology, number 220.

Data from liver and kidney histology were presented in the second abstract:

Rodrigues, GZP; Staudt, LBM; Silva, JCG; Dallegrave, E; Bigolin, C; Burghausen, JH; Betti, AH; Gehlen, G. Hepatic and renal histopathological evaluation of cf-1 mice treated with different doses of meloxicam. Section Biomarkers, number 85.

From these abstracts, it was verified a need for further analysis, resulting in the present article.

Disclosure statement

The authors declare that there is not any conflict of interest.

Additional information

Funding

This work was supported by National Council for Scientific and Technological Development (CNPq); Coordination for the Improvement of Higher Education Personnel (CAPES) and Feevale University.