Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules

• Published in: Drug delivery Vol. 30; no. 1; p. 2241661
• Main Authors: Iqubal, Ashif, Najmi, Abul Kalam, Md, Shadab, Alkreathy, Huda Mohammed, Ali, Javed, Syed, Mansoor Ali, Haque, Syed Ehtaishamul
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis Ltd 01.12.2023; Taylor & Francis; Taylor & Francis Group
• Subjects: Animals; Apoptosis; Caspase 3 - metabolism; Creatinine; Cyclophosphamide - adverse effects; Cytokines; Fibrosis; Growth factors; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Kidney - metabolism; Mice; Nephrotoxicity; NF-kappa B - metabolism; Oxidative Stress; renal fibrosis and inflammation; Toxicity; Urea - metabolism; renal fibrosis and inflammation; Nephrotoxicity; oxidative stress
• ISSN: 1071-7544; 1521-0464
• DOI: 10.1080/10717544.2023.2241661

Cyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. and was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP ( ), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection ( ). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study's outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1β (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the study when treated with NERO 400 and compared with CP 200. study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-β-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-β1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson's' trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.