The role of oxidative stress and antioxidant therapy in cisplatin neurotoxicity: preclinical evidence in the last decade

Cisplatin remains one of the most effective chemotherapeutic agents for the treatment of several tumors. However, its use is limited by dose-dependent and cumulative neurotoxicity, which affects the peripheral nervous system, hypothalamus, prefrontal cortex, cerebellum, retina and optic nerve. Currently, there is no neuroprotective strategy against cisplatin-induced neurotoxicity. Studies in the last decade have consolidated the role of oxidative stress as a central molecular event in cisplatin-induced neurotoxicity. A wide array of antioxidant-based strategies from natural compounds to repurposed drugs has been investigated in animal models as neuroprotective agents. In general, these compounds act directly through free radical scavenging, or indirectly, by activating the Nrf2 pathway, which induces the expression of antioxidant defense enzymes. This review approaches the role of oxidative stress in preclinical studies on cisplatin-induced neurotoxicity from the last decade, and evaluates the most promising antioxidant interventions, with the focus on cognitive impairment, peripheral neuropathy, ocular toxicity, anxiety and depression. The link between cisplatin neurotoxicity and neurodegenerative diseases as well as the emerging novel therapeutic strategies to replace cisplatin chemotherapy are discussed. The need for future studies in tumor-bearing animal models to investigate interferences with the antitumor efficacy of cisplatin is pointed out as a critical requirement for clinical translation.