Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation

J Pain. 2021 Aug;22(8):996-1013. doi: 10.1016/j.jpain.2021.03.142. Epub 2021 Mar 24.

Abstract

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.

Keywords: Neuropathy; TLR4, chemotherapy; antioxidants; cytokines; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antioxidants / pharmacology*
  • Disease Models, Animal
  • Hyperalgesia* / chemically induced
  • Hyperalgesia* / drug therapy
  • Hyperalgesia* / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / drug therapy*
  • Neuroinflammatory Diseases* / chemically induced
  • Neuroinflammatory Diseases* / drug therapy
  • Neuroinflammatory Diseases* / immunology
  • Neuroinflammatory Diseases* / metabolism
  • Oxaliplatin / adverse effects*
  • Oxidative Stress / drug effects*
  • Peripheral Nervous System Diseases* / chemically induced
  • Peripheral Nervous System Diseases* / drug therapy
  • Peripheral Nervous System Diseases* / prevention & control
  • Spinal Cord* / drug effects
  • Spinal Cord* / immunology
  • Spinal Cord* / metabolism
  • Toll-Like Receptor 4

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Oxaliplatin