Agomelatine prevents gentamicin nephrotoxicity by attenuating oxidative stress and TLR-4 signaling, and upregulating PPARγ and SIRT1

Kidney injury is a relatively common complication of the use of aminoglycosides. Inflammation and oxidative stress play a key role in gentamicin (GM) nephrotoxicity. We investigated the protective effect of the melatonergic agonist agomelatine (AGM) on GM nephrotoxicity, emphasizing the involvement of TLR-4 signaling, SIRT1 and PPAR gamma. Rats received 25 mg/kg AGM for 15 days and 100 mg/kg GM for eight days starting at day 7. Elevated serum creatinine, urea and Kim-1 along with multiple histological alterations in the kidney were observed in GM-intoxicated rats. Malondialdehyde (MDA), TNF-alpha, IL-1 beta, nitric oxide (NO) and myeloperoxidase (MPO) were increased, and GSH, SOD and catalase were decreased in the kidney of GM-intoxicated rats. Treatment with AGM significantly ameliorated the kidney function biomarkers, prevented tissue injury, decreased inflammatory cytokines, MDA, NO and MPO, and boosted antioxidants. In addition, AGM suppressed the expression of TLR-4, NF-KB p65, p38 MAPK, ERK-1, VCAM-1 and iNOS, whereas upregulated SIRT1 and PPAR gamma in the kidney of GM-intoxicated rats. In conclusion, AGM prevented GM nephrotoxicity in rats by attenuating oxidative injury and inflammation. AGM suppressed TLR-4 signaling, enhanced antioxidants and upregulated SIRT1 and PPAR gamma in the kidney of GM-induced rats.

Automated summary

This study demonstrated that the melatonergic agonist agomelatine is protective against gentamicin-induced kidney injury in rats by reducing oxidative stress and inflammation. AGM suppressed TLR-4 signaling, increased antioxidants, and upregulated SIRT1 and PPAR gamma in the kidney of GM-intoxicated rats.