Luteolin Abates Ifosfamide-Induced Nephrotoxicity by Downregulating Renal Oxidative DNA Damage, Inflammation, and Apoptosis in Experimental Rats

SUMMARY:

Ifosfamide (IFO) is considered as a broad-spectrum antineoplastic drug used in the management of multiple malignancies. However, its use is limited by its associated nephrotoxicity. This work aimed to examine the nephroprotective effect of luteolin against IFO-induced nephrotoxicity. Our study was divided into four groups (n=6); Control group; Luteolin group: Rats were administered luteolin at a dosage of 10 mg/kg intraperitoneally (i.p.) daily for seven days; IFO group: Rats were administered a single intraperitoneal dosage of 500 mg/kg body weight on the sixth day; and IFO+luteolin group: Rats were administered both drugs. Biochemical analyses of serum creatinine and blood urea nitrogen (BUN) were performed. Renal homogenate supernatant was used to estimate levels of the antioxidant enzyme superoxide dismutase (SOD) and the lipid peroxidation marker malonaldehyde (MDA). Furthermore, histopathological examination of renal tissues and immunohistochemical examination of nuclear factor kappa (NF-kβ), interleukin 1- beta (IL-1β), myeloperoxidase (MPO), and caspase-3 were conducted. Protein levels of tumor necrosis factor-alpha (TNF-α), interleukin- 6 (IL-6), and 8-hydroxy-2´-deoxyguanosine (8-OHdG) were assessed by ELISA, and gene expression of Bcl-2 associated protein x (Bax), heme oxygenase-1 (HO-1), and nuclear factor erythroid 2 related factor 2 (Nrf2) were measured by RT-PCR. The results revealed that the combination of luteolin and IFO significantly decreased levels of creatinine, BUN, MDA, TNF-α, NF-kβ, IL-1β, 8-OHdG, IL- 6, Bax, and caspase-3. Meanwhile, it upregulated Nrf2, HO-1, and SOD levels compared to the IFO group. Additionally, there was an improvement in renal histological morphology. These findings indicate that combined treatment with luteolin and IFO mitigates IFO- induced nephrotoxicity through its antioxidant, anti-inflammatory, and antiapoptotic properties.