Schwingel Tania E, Klein Caroline P, Nicoletti Natalia F, Dora Cristiana L, Hadrich Gabriela, Bica Cláudia G, Lopes Tiago G, da Silva Vinicius Duval, Morrone Fernanda B
Programa de Pós Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2014 Sep;387(9):837-48. doi: 10.1007/s00210-014-0994-0. Epub 2014 Jun 8.
Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds--rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)--daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.
奥沙利铂（OXA）是一种铂类化合物，广泛用于治疗某些实体瘤，尤其是结直肠癌。尽管其疗效显著，但奥沙利铂相关的神经毒性是该药物的主要剂量限制因素，迄今为止，尚无合适的治疗方法。奥沙利铂化疗还会增加发生具有炎症活性的肝损伤的几率，即化疗相关脂肪性肝炎（CASH）。在本研究中，我们旨在比较一系列抗氧化化合物对小鼠奥沙利铂诱导的肝毒性和神经毒性同时发生的影响。将BALB/c小鼠腹腔注射奥沙利铂，剂量为10mg/kg，持续6周，导致机械性异常性疼痛和肝脂肪变性。我们通过灌胃每日给BALB/c小鼠施用以下抗氧化化合物——芦丁（RT）（20mg/kg）、白藜芦醇（RVS）（100mg/kg）、槲皮素（QT）（20mg/kg）和槲皮素纳米乳剂（NQT）（20mg/kg），并使用N-乙酰半胱氨酸（NAC）作为阳性对照。与奥沙利铂组相比，用RVS、RT或NQT治疗能够预防机械性异常性疼痛，并且这种作用与腰脊髓中c-Fos免疫阳性率降低有关。关于对脂肪性肝炎的影响，RVS、QT和NQT几乎完全逆转了奥沙利铂诱导的平均肝脏重量增加。根据这些先前的数据，组织学评估表明RSV、RT、QT和NQT组中评估的肝脂肪变性的所有特征均有所减轻。这些化合物能够降低凋亡标志物半胱天冬酶-3的免疫阳性率。另一方面，只有QT和NQT治疗能够降低通过髓过氧化物酶（MPO）活性测量的中性粒细胞迁移。这些结果表明，所测试的化合物RVS、RT、QT和NQT可用于临床治疗奥沙利铂诱导的神经毒性和肝毒性。
