Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil.
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
J Pain. 2021 Aug;22(8):996-1013. doi: 10.1016/j.jpain.2021.03.142. Epub 2021 Mar 24.
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.
化疗诱导性周围神经病（CIPN）是一种常见的、难以治疗的、与奥沙利铂（OXA）治疗相关的剂量限制的副作用。在这项研究中，我们评估了三种抗氧化剂——即 N-乙酰半胱氨酸、α-硫辛酸和维生素 E——对荷瘤瑞士小鼠模型中 OXA 的痛觉参数和抗肿瘤疗效的影响。抗氧化剂的口服治疗在与 OXA 同时给药时抑制了机械性和冷性痛觉过敏（预防方案），以及在先前建立的 CIPN 动物中（治疗方案）。OXA 增加了活性氧（ROS）的产生和脂质过氧化，增加了脊髓中促炎细胞因子（IL-1β和 TNF-α）的含量和星形胶质细胞标记物 Gfap mRNA 的表达。抗氧化剂降低了 ROS 的产生和脂质过氧化，消除了 OXA 处理动物的神经炎症。用 OXA 治疗的 Toll 样受体 4（Tlr4）和炎性小体酶 caspase-1/11 敲除小鼠显示，脊髓中促炎细胞因子（但不是氧化应激）水平降低，这与对 OXA 诱导的机械性痛觉过敏的抗性有关。最后，抗氧化剂在体内既不影响 OXA 的抗肿瘤活性，也不影响其血液学毒性。本研究结果提示进一步评估抗氧化剂在临床管理化疗诱导性周围神经病中的作用。观点：本研究报告了口服给予抗氧化剂（N-乙酰半胱氨酸、α-硫辛酸和维生素 E）在减轻荷瘤小鼠奥沙利铂诱导的周围神经病方面的预防和治疗效果。抗氧化剂的抗痛觉作用与抑制 ROS 依赖性神经炎症有关，且不会损害 OXA 的抗肿瘤活性，因此表明这些化合物具有转化潜力。
