Protective Effects of Mirazid on Gentamicin-induced Nephrotoxicity in Rats through Antioxidant, Anti-inflammatory, JNK1/ iNOS, and Apoptotic Pathways; Novel Mechanistic Insights

Background: As the use of Gentamicin became more widespread, the drug’s harmful effects, particularly nephrotoxicity, became increasingly well-known. Antibacterial and anti-inflammatory properties have long been associated with Mirazid. The goal of this research was to find out more about frameworks for the protection of Mirazid against nephrotoxicity triggered by Gentamicin.

Methods: Three groups of albino male rats were created; the normal group received only saline. In the second group, nephrotoxicity was produced for 10 days with Gentamicin (100 mg/kg; i.p.). In the third group; Mirazid (10 mg/kg; p.o.) was administered for 10 days before receiving Gentamicin. This was done to investigate the kidney/body weight index, serum creatinine, urea, lactate dehydrogenase (LDH), malondialdehyde (MDA), and Glutathione (GSH) levels. Moreover, immunohistochemical staining was done to study Jun N- terminal kinase 1 (JNK1), inducible nitric oxide synthase (iNOS), and caspase3 expressions along with histopathological changes. Additionally, a molecular docking study was performed for the seventeen isolated and identified compounds from myrrh, JNK1 is inhibited by an oleo-gum resin derived from the Commiphora species of plants (Burseraceae).

Results: The Gentamicin group showed an increase in kidney/ body weight index, serum creatinine, urea, LDH, and MDA, while decreasing GSH levels. Furthermore, immunohistochemical staining revealed increased JNK1, iNOS, and caspase3 expressions along with histopathological changes. All of these indicators were significantly reduced by mirazid, which also restored oxidant/antioxidant hemostasis. Furthermore, the histological architecture of tissues has been significantly conserved. Concerning the docking study, the isolated compound (12) was found to be superior to the co-crystallized inhibitor (18) with a binding score of -7.19 kcal/mol compared to -6.95, respectively.

Conclusion: Mirazid was found to be a potential method for suppressing the nephrotoxicity caused by Gentamycin by inhibiting the JNK1/ iNOS pathways, therefore preserving kidney function. The antioxidant, anti-inflammatory, and anti-apoptotic properties of mirazid are thought to be responsible for its preventive efficacy.