Análise do papel protetor do complexo [6]-gingerol-β-ciclodextrina frente à nefrotoxicidade induzida por cisplatina

Abstract

Cisplatin is an antineoplastic agent effective in several cancers; however, due to its nephrotoxicity its use is limited. Acute kidney injury (AKI) induced by this drug is caused by inflammation, apoptosis and oxidative stress in renal tubular cells. Therefore, treatment with compounds like [6]-gingerol, derived from ginger (Zingiber officinale), which has anti-inflammatory and antioxidant properties protects the kidney from cisplatin induced-AKI. This substance has low solubility. Complexation with β-cyclodextrin (β-CD) was proposed here to increase the solubility of [6]-gingerol. This complexation could reduce [6]-gingerol dose compared to other studies found in the literature. In addition, it would preserve the therapeutic response against cisplatin-induced AKI and, consequently, improving its oral bioavailability. This study evaluated the protective effect of [6]-gingerol complexed with β-cyclodextrin upon renal damage caused by cisplatin treatment in female mice. The minimal dose necessary to induce AKI via cisplatin treatment was established by a dose-response curve performed with the following concentrations: 10, 12.5, 15 and 17 mg/kg. Our results demonstrated that the 15 mg/kg dose of cisplatin was the best dose to induce AKI for the following experiments. Female Swiss mice (n= 6-8) were divided into 5 groups: control, cisplatin, N-acetylcysteine (NAC) 120 mg/kg and [6]-gingerol-β-CD at doses of 6.25, 12.5 and 25 mg/kg. Treatments were administered orally, for 5 days. At the 3rd day, 1h after treatment, cisplatin was administered (i.p.). After 5 days animals were euthanized. All parameters investigated were altered by cisplatin treatment, compared to the control group: plasma creatinine (0.81 ± 0.124 mg/dL), plasma urea (135.7 ± 20.75 mg/dL), creatinine clearance (1.74 ± 0.402 ml/min/kg), urinary Gamma-GT (2.18 ± 0.247 U/mg creatinine), urinary protein (154.1 ± 4.78 mg/dL), MPO (8.85 ± 1.101 UMPO/mg tissue), GSH (1410.0 ± 57.42 GSH/mg of tissue). Treatment with 25 mg/kg of [6]-gingerol-β-CD reversed nephrotoxicity, considering all parameters mentioned above. Similar results were obtained with treatment with 12.5 mg/kg of [6]-gingerol-β-CD, except for MPO activity. Compared to the AKI group, the treatment with [6]-gingerol-β-CD reduced the expression of KIM-1 by 5.47fold, CxCL-1 by 3.38fold, NF-κB by 1.7fold, and Hemox-1 by 4,16fold. Conversely, treatment with [6]-gingerol-β-CD increase SOD1 expression 1.72fold. In conclusion, the present study managed to establish a model of AKI induced by cisplatin in female mice. Additionally, our results indicates that treatment with [6]-gingerol-β-CD complex at the doses of 12.5 and 25 mg/kg protected renal function against cisplatin-induced nephrotoxicity in female mice. We suggest that [6]-gingerol-β-CD complex acts as an anti-inflammatory agent by blocking NF-κB mRNA expression and as an antioxidant agent by stimulating the expression of genes related to the Nrf2 signaling pathway.