Contribution of Reactive Oxygen Species to Cisplatin-Induced Peripheral Neurotoxicity

Objectives: Cisplatin is an effective platinum-based chemotherapeutic drug which is used to treat various forms of cancer. While cisplatin does not cross the blood brain barrier, it infiltrates the peripheral nervous system affecting the dorsal root ganglia (DRG) and peripheral nerves resulting in hypoesthesia and pain. We hypothesize the accumulation of reactive oxygen species (ROS) contributes to cisplatin-induced neurotoxicity. Our previous data demonstrate that co-injection of cisplatin (1mg/kg, for 7 days) with a reactive oxygen species scavenger (PBN) (100 mg/kg, for 7 days) attenuated cisplatin evoked hyperalgesia in a murine model of cisplatin-evoked hyperalgesia. Our research focuses on the impact of ROS on cisplatin-induced neurotoxicity on DRG neurons in vitro.
Methods: Immunohistochemistry (IHC) and intracellular calcium imaging were used to determine effects of cisplatin (13uM) and ROS scavenger phenyl-N-t-butyl nitrone (PBN, 100 mM) on small cultured DRG neurons (cell area < 500microns2), most likely nociceptors.
Results: Small DRG neurons treated with cisplatin for 24 hrs demonstrate increased basal calcium and responsiveness to subthreshold concentration of KCL (25mM, 15 s). Co-treatment of cisplatin with PBN overnight normalized basal calcium, and acute application of PBN for 1 hr decreased responsiveness of neurons to 25 mM KCl. Cisplatin also decreased neurite outgrowth and co-treatment of cisplatin with PBN attenuated this effect of in a population of peripherin-positive DRG neurons.
Conclusions: We observed increased basal calcium and stimulus response rates, and decreased neurite outgrowth when small DRG neurons were treated with cisplatin in vitro. These effects offer a possible explanation to the observed symptoms in cisplatin-induced peripheral neuropathy. The attenuation of the neurotoxic effects of cisplatin by PBN supports our hypothesis that ROS play a significant role. Together, we provide evidence that ROS impacts cisplatin-induced neurotoxicity, and ROS scavengers may represent a new strategy for alleviating the side effects of chemotherapy.