Mechanistic Insights into Oxaliplatin-Induced Neurotoxicity: Role of Oxidative Stress, Apoptosis, and Neurobehavioral Impairments in Drosophila melanogaster

Abstract

Cancer is a major global health burden and the second leading cause of death worldwide. The notable increase in life expectancy rates can be attributed to recent advancements in adjuvant antineoplastic therapy. Oxaliplatin is a widely used platinum-based drug for colorectal cancer treatment. However, long-term use of these medications is associated with neurotoxicity, which is regarded as one of the side effects that limits dosage. Drosophila melanogaster is an ideal model organism due to its short generation time, low maintenance costs, and well-characterized genome and is extensively employed to investigate neurological disorders, DNA damage, oxidative stress, and apoptosis-like mechanisms are analogous to mammalian systems. We aimed to examine the toxic effects of Oxaliplatin on Drosophila model in larva and adult. Behavioral alterations, developmental cycle, and biochemical changes were monitored. In adult flies, there was pharmacological toxicity by platinum-DNA adduct formation, gut cytoskeletal disruptions, and DNA damage. Reactive Oxygen Species accumulation and apoptosis were identified in the adult flies’ gut and brain. In case of Drosophila larva, oxidative stress in the brain imaginal disc and gut was accompanied by abnormalities in their crawling, righting, and cold tolerance behaviors. Dysregulated mRNA levels of antioxidant genes and apoptotic genes was found according to age. Our results strive to understand the thorough toxicity of Oxaliplatin not described in earlier studies.