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. This study aimed to investigate the frameworks for the protection of Mirazid against nephrotoxicity triggered by Gentamicin. Methods: Male albino rats were divided into three groups; the normal group received only saline. Nephrotoxicity was induced by Gentamicin (100 mg/kg; i.p.) for 10 days in the second group. 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, which is an oleo-gum resin obtained from the Commiphora species of plants (Burseraceae) against JNK1. 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. Mirazid showed a significant decrease in all of these parameters and restored oxidant/antioxidant hemostasis. In addition, it has significantly preserved the histopathological architecture of tissues. 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: Current data demonstrated that Mirazid represented a viable approach to suppress the nephrotoxicity produced by Gentamycin through inhibiting JNK1/ iNOS pathways, thus preserving kidney function. Mirazid prophylactic efficacy is assumed to be due to its antioxidant, anti-inflammatory, and anti-apoptotic qualities.