Quillaja saponin mitigates methotrexate-provoked renal injury; insight into Nrf-2/Keap-1 pathway modulation with suppression of oxidative stress and inflammation

• Published in: Journal of pharmaceutical health care and sciences Vol. 10; no. 1; p. 17
• Main Authors: Abdel-Reheim, Mustafa Ahmed, Ali, Merhan E, Gaafar, Ahmed Gaafar A, Ashour, Ahmed Amine
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.04.2024; BioMed Central; BMC
• Subjects: Acids; Animals; Antioxidants; Apoptosis; Biomarkers; Cell death; Creatinine; Cytokines; Drug dosages; Gene expression; Health aspects; Immunotherapy; Inflammation; Kidney diseases; Kidneys; Laboratory animals; Methotrexate; Oxidative stress; Pathological kidney; Pathology; Product information; Quillaja saponaria; Saponins; TNF-α/Nrf-2/Keap-1; Toxicity; Tumor necrosis factor-TNF; Egypt; Nevada; Cairo Egypt; St Louis Missouri; United States > US; Oxidative stress; Methotrexate; TNF-α/Nrf-2/Keap-1; Pathological kidney; Quillaja saponaria; Apoptosis
• ISSN: 2055-0294; 2055-0294
• DOI: 10.1186/s40780-024-00330-4

Methotrexate (MTX) is an antineoplastic/immunosuppressive drug, whose clinical use is impeded owing to its serious adverse effects; one of which is acute kidney injury (AKI). Most of MTX complications emerged from the provoked pro-oxidant-, pro-inflammatory- and pro-apoptotic effects. Quillaja saponaria bark saponin (QBS) is a bioactive triterpene that has been traditionally used as an antitussive, anti-inflammatory supplement, and to boost the immune system due to its potent antioxidant- and anti-inflammatory activities. However, the protective/therapeutic potential of QBS against AKI has not been previously evaluated. This study aimed to assess the modulatory effect of QBS on MTX-induced reno-toxicity. Thirty-two male rats were divided into 4-groups. Control rats received oral saline (group-I). In group-II, rats administered QBS orally for 10-days. In group-III, rats were injected with single i.p. MTX (20 mg/kg) on day-5. Rats in group-IV received QBS and MTX. Serum BUN/creatinine levels were measured, as kidney-damage-indicating biomarkers. Renal malondialdehyde (MDA), reduced-glutathione (GSH) and nitric-oxide (NO ) were determined, as oxidative-stress indices. Renal expression of TNF-α protein and Nrf-2/Keap-1 mRNAs were evaluated as regulators of inflammation. Renal Bcl-2/cleaved caspase-3 immunoreactivities were evaluated as apoptosis indicators. Exaggerated kidney injury upon MTX treatment was evidenced histologically and biochemically. QBS attenuated MTX-mediated renal degeneration, oxidant-burden enhancement, excessive inflammation, and proapoptotic induction. Histopathological analysis further confirmed the reno-protective microenvironment rendered by QBS. In conclusion, our results suggest the prophylactic and/or therapeutic effects of QBS in treating MTX-induced AKI. Such reno-protection is most-likely mediated via Nrf-2 induction that interferes with oxidant load, inflammatory pathways, and proapoptotic signaling.