Nephroprotective effects of febuxostat and/or mirtazapine against gentamicin-induced nephrotoxicity through modulation of ERK 1/2, NF-κB and MCP1

ABSTRACT

Objectives

This study was conducted to evaluate the potential nephroprotective effects of febuxostat, mirtazapine, and their combination against gentamicin-induced nephrotoxicity.

Methods

Induction of nephrotoxicity was achieved via gentamicin injection (100 mg/kg, I.P., for 7 days). Two different doses of mirtazapine (15–30 mg/kg), febuxostat (5–10 mg/kg), and their combination were administered daily for 14 days prior to gentamicin injection and then concomitantly with gentamicin for additional 7 days. Nephrotoxicity was evaluated histopathologically and biochemically. Renal caspase-3, extracellular signal-regulated protein kinase 1/2 (ERK1/2), nuclear factor-kappa-β (NF-κβ), and monocyte chemoattractant protein (MCP-1) were assayed.

Results

Febuxostat and mirtazapine significantly (p < 0.05) alleviated biochemical and histopathological alterations that were induced by gentamicin and, for the first time, significantly decreased the renal levels of ERK1/2 and MCP-1. Conclusion: Febuxostat and mirtazapine were found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.

Expert opinion

The utility of nonpurine xanthine oxidase inhibitor, such as febuxostat and mirtazapine are offering a new potential opportunity for the future nephroprotective effects therapy: Febuxostat and mirtazapine are found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.

KEYWORDS:

• Gentamicin
• Nephrotoxicity
• Mirtazapine
• Febuxostat
• NF-κβ
• ERK 1/2
• MCP-1

Acknowledgments

The authors would like to thank Dr. Rehab Ahmed Abdel Moneim, Associate Professor in Histology and Cell Biology and Dr. Marwa Mohamed Essawy, Oral Pathology Department, Faculty of Dentistry, Alexandria University, Egypt. Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Egypt. For helping in histopathlogical examination of kidney tissue and renal caspase −3 immunohistochemical examination.

Authors’ contributions

El-Sisi and Sokar conceived and designed the experiments. Abu-Risha and Shalaby conducted the experiments, analyzed the data, and composed the manuscript. All the authors read and approved the final manuscript.

The authors declare that all data were generated in-house and that no paper mill was used.

Declaration interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Compliance with ethical standards

The experimental work described in this study complies with guidelines for the care and the use of laboratory animals and the ethical principles adopted by the ‘Research Ethics Committee’, Faculty of Pharmacy, Tanta University.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors