Potencial nefroprotetor do 8-gingerol isolado do gengibre (Zingiber officinale Roscoe) frente à toxicidade induzida por cisplatina

Abstract

Cisplatin (CIS) is a chemotherapeutic agent potentially nephrotoxic. Despite preventive strategies, it is capable of causing acute kidney injury (AKI) in 20-30% of patients. AKI, the major side effect and limiting factor of cisplatin therapy, is triggered by oxidative damage, inflammation and apoptosis of renal tubular cells. Ginger (Zingiber offinale Roscoe) is a promising source of therapeutic substances. Gingerois isolated from ginger have antioxidant and anti-inflammatory properties with possible nephroprotective potential. The present study sought to investigate the effects of 8-gingerol (8-G) on CIS-induced AKI. First, a dose response curve (5, 12, 20, and 25 mg/kg i.p.) was made to define the dose of CIS able of causing AKI. In terms of nephrotoxicity, the results were similar for the doses of 20 and 25 mg/kg. Then, we chose the lowest of them. For the second block of experiments, which consisted of the treatment of AKI with the compound 8-G, the animals were divided into 5 groups (n=6-8): control, CIS, NAC (N-acetylcysteine) 120 mg/kg (positive control), 8-G 25 mg/kg and 8-G 50 mg/kg. All tested substances were administered i.p. for 5 days and on the day 3, 1h after the last treatment, CIS was administered. At the end of the 5 days’ experiment, the animals were euthanized. CIS altered all parameters investigated in comparison to the saline treated group: serum creatinine (1.3 ± 0.26 vs 0.28 ± 0.014 mg/dL), serum urea (198.0 ± 23.2 vs 36.4 ± 3.8 mg/dL), creatinine clearance (0.9 ± 0.21 vs 3.12 ± 0.31 ml/min/kg), urinary gama GT (4.86 ± 0.30 vs 0.58 ± 0,21 U/mg creatinine), urinary albumin (0.05 ± 0.008 vs 0.0048 ± 0.0009 mg/24h), urinary protein (2.6 ± 0.24 vs 1.26 ± 0.16 mg/24h), renal GSH (108.1 ± 9.3 vs 244.6 ± 13.17 μg GSH/mg tissue), urinary MDA (54.95 ± 3.6 vs 35.03 ± 2.7 nmol/mg creatinine), renal MPO (8.11 ± 1.27 vs 4.0 ± 0.6 UMPO/mg tissue), GsR gene expression (0.44 ± 0.11 vs 1.27 ± 0.21), KIM-1 (2.38 ± 0.31 vs 0.98 ± 0.11), NGAL (9.89 ± 2.09 vs 1.092 ± 0.41) and IL-1β (4.39 ± 1.20 vs 1.09 ± 0.30) in addition to renal histology, thus reproducing AKI in the animals. Treatment with 8-G at a dose of 25 mg/kg was not able to reduce nephrotoxicity. However, the doses of 50 mg/kg attenuated most of the parameters measured here: serum creatinine (0.6 ± 0.10 mg/dL), serum urea (105.3 ± 19.7 mg/dL), creatinine clearance (1.72 ± 0.3 ml/min/kg), urinary gama GT (3.10 ± 0.89 U/mg creatinine), urinary albumin (0.03 ± 0.007 mg/24h), urinary protein (2.05 ± 0.23 mg/24h), renal GSH (162.2 ± 19.0 μg GSH/mg tissue), urinary MDA (45.7 ± 1.4 nmol / mg creatinine), renal MPO (4.61 ± 0.43 UMPO/mg tissue), the gene expression of GsR (0.93 ± 0.18) and IL-1β (0.5 ± 0.08 mg/dL). NAC treatment significantly improved damage by significantly increasing renal GSH concentrations (197.3 ± 10.44 μg GSH/mg tissue) and GsR gene expression (9.95 ± 1.3), reduce plasma creatinine (0.5 ± 0.08 mg/dL) and renal MPO activity (3.07 ± 0.32 UMPO/mg tissue), KIM-1 expression (1.47 ± 0,16) and histopathological changes. The present study was able to reproduce the CIS-induced AKI model and confirm the nephroprotective action of NAC in this model. 8-G in turn, at the highest dose employed, also provided protection, but less significantly than NAC. Therefore, we conclude that 8-G in the dose used here also has a protective effect and may serve as an adjuvant in preventing CIS-induced nephrotoxicity in ARF.