Vincamine protects against cisplatin induced nephrotoxicity via activation of Nrf2/HO-1 and hindering TLR4/ IFN-γ/CD44 cells inflammatory cascade

• Published in: Life sciences (1973) 2021-05, Vol.272, p.119224, Article 119224
• Main Authors: El-Sayed, Rehab M., Abo El Gheit, Rehab E., Badawi, Ghada A.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Apoptosis - drug effects; CD44 antigen; Cisplatin; Cisplatin - adverse effects; Cisplatin - pharmacology; Cisplatin - toxicity; Creatinine; DNA fragmentation; Growth factors; Heme Oxygenase-1 - metabolism; HO-1; Hyaluronan Receptors - metabolism; Inflammation; Interferon; Interferon-gamma - metabolism; Kidney - drug effects; Kidney - metabolism; Kidneys; Male; Malondialdehyde; Molecular modelling; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Nrf2; Oxidants; Oxidative Stress - drug effects; Oxidizing agents; Peroxidase; Pretreatment; Protective Agents - pharmacology; Rats; Signal Transduction - drug effects; Solid tumors; TGFβ1; TLR4; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transforming growth factor-b; Transforming growth factor-b1; Tumors; Urea; Vincamine; Vincamine - pharmacology; γ-Interferon
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119224

Cisplatin is a commonly prescribed chemotherapeutic agent for the treatment of different types of solid tumors. However, the high incidence of cisplatin-induced nephrotoxicity largely restricts its clinical efficacy in absence of both preventive and treatment options to combat its serious and life-threatening effects. Therefore, the current study investigated the reno-protective molecular mechanisms of vincamine against cisplatin nephrotoxicity. Vincamine (40 mg/kg P.O.) was given for 7 days, cisplatin was injected as single dose (10 mg/kg i.p.) at the seven day of the experiments. Animals were sacrificed after 72 h of cisplatin injection to allow nephrotoxicity. Vincamine pretreatment improved kidney functions and decreased kidney function tests as urea, creatinine and kidney injury molecule-1 (KIM-1), as well as it exhibited antioxidant properties by restoring balance between pro and anti-oxidants of malondialdehyde (MDA), myeloperoxidase (MPO), nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). Moreover, vincamine hindered the inflammatory cascade via mediating Toll like receptor 4 (TLR4)- interferon gamma (IFNγ)-CD44 cells pathway and transforming growth factor beta (TGFβ1). Additionally, vincamine retained DNA fragmentation. In conclusion, vincamine represents a promising intervention in limiting cisplatin nephrotoxicity by its anti-oxidant, anti-inflammatory, antiapoptotic mechanistic activities. Therefore, vincamine can be used as adjunct therapy with cisplatin to mitigate cisplatin-induced-AKI. •This study investigates the reno-protective effect of vincamine in cisplatin treated rats.•Vincamine confirmed its antioxidant effect by via activation of Nrf2/HO-1 pathway.•The anti-inflammatory effect of vincamine was verified by hindering renal TLR4- IFN-γ- CD44.•Vincamine reduce fibrosis activation through inactivation TGFβ1.