Ramelteon and mechanism of its restorative effect in an experimental lung disease model

Abstract

Methotrexate (MTX) is an anticancer agent widely used in clinical practice for various oncological, rheumatological, autoimmune, and inflammatory diseases. However, the side effects of MTX limit its usage for treatment. In addition, diffuse alveolar damage, interstitial pneumonia, fibrosis, and pleural reactions may be encountered in MTX-induced pulmonary toxicity. Ramelteon (RML), a melatonin receptor agonist, has antioxidant, anti-inflammatory, and protective effects are shown by several studies. This study aimed to show the antioxidant, anti-inflammatory, and antiapoptotic effects of RML and its effect on the airway surface liquid volume homeostasis via aquaporins (AQP) in MTX-induced lung injury. Thirty-two female Wistar Albino rats were grouped into four groups as control, MTX (20 mg/kg, intraperitoneally, a single dose), MTX + RML, and RML (10 mg/kg, via oral gavage, for seven days) groups. Once the experiment ended, the rats’ lung tissues were taken for biochemical, genetic, histopathological, and immunohistochemical examinations. MTX significantly increased oxidative stress index and total oxidative status, and decreased total antioxidant status levels by 202.0%, 141.4%, 20.2%, respectively, relative to the control (p ˂ 0.001 for all). AQP-1/5, which is an indicator of lung damage, was also found to decrease significantly (p ˂ 0.001). In addition, a significant increase was observed in interleukin-1β, interferon-beta, and caspase-8 expressions and histopathological changes as a result of immunohistochemical and histochemical examinations (p ˂ 0.001). RML treatment ameliorated all these changes and significantly regressed lung damage. Our results suggest that RML might be used as a lung-protective agent in various models of lung and tissue injury.

Keywords:

• Methotrexate
• Ramelteon
• Lung
• Apoptosis
• Inflammation
• Oxidative stress
• Aquaporin

Acknowledgments

We appreciate the support of the staff of the Experimental Animals and Medical Research Application and Research Center, Süleyman Demirel University, Isparta, Turkey.

Ethical approval

The Local Ethical Committee on Animal Research of Süleyman Demirel University approved all experiments involving animals.

Author contributions

İA: Conceptualization, Methodology, Writing and Editing. HA: Data curation; Investigation, Writing and Editing. YE: Methodology, Writing and Editing. SÖ: Investigation, Writing and Editing. NH: Investigation, Writing and Editing. DKD: Methodology, Writing and Editing. GO: Methodology, Writing and Editing. AV: Methodology, Writing and Editing. The final manuscript was read and approved by all authors.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets, which are applied or analyzed in the present research, are accessible through the corresponding author upon the acceptable request.

Additional information

Funding

The Scientific Research Projects Coordination Unit of Süleyman Demirel University supported this research with project code TSG-2020-8134.