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DNA Damage and Oxidative Stress Response in The Human Neuroblastoma SH-SY5Y Cell Line Exposed to Clinically Relevant doses of Ketamine

Introduction: Ketamine is a dissociative anaesthetic used to induce general anaesthesia in certain medical procedures. Considering the dissociative and sedative properties of ketamine, it has also been used as a recreational drug in a variety of social settings. Ketamine abuse displays neurobehavioral alterations such as depression, anxiety, cognition deficits, and schizophrenia. While the exact mechanism is still unclear, some findings suggest that oxidative stress and genotoxic properties may be implicated in ketamine- induced neurological impairment. Methods: The aim of this study was to explore the effects of exposure to ketamine depending on selected concentrations used during general anaesthesia, analgesia or drug-abuse available from the literature. Human neuroblastoma SH-SY5Y cells were treated with ketamine at concentrations of 0.09, 0.37 and 1.49 mg/L. Cell viability was studied using the MTS assay. We measured biomarkers of oxidative stress [malondialdehyde (MDA), reactive oxygen species (ROS) production and glutathione (GSH) levels] and primary DNA damage (using the alkaline comet assay) as the endpoints that can be disrupted following ketamine use. Results: After a 24-hour treatment, the applied concentrations reduced cell viability up to 30 %. Although no changes in the concentration of MDA and GSH were observed, a significant decrease in ROS levels was determined after exposure to 0.37 and 0.09 mg/L of ketamine in comparison to control cells. Ketamine treatment at all of the tested concentrations resulted in a significant increase of primary DNA damage versus negative control. However, no significant differences between the applied concentrations were found. Conclusion: Considering that SH-SY5Y cells originated from neural tissue, the findings regarding genotoxic potency of ketamine in vitro call for concern, especially in light of the possible neurotoxic effects that may be relevant in in vivo conditions. Their extent and outcomes could be further elucidated using other molecular biology and cytogenetic methods and experimental models. Funding: This research was supported by the programme of cooperation between the Institute for Medical Research and Occupational Health (Zagreb, Croatia) and the University North (Varaždin, Croatia) and the Croatian Science Foundation’s grant number HrZZ- UIP-2017-05-7260.

ketamine ; neurotoxicity ; DNA damage ; oxidative response

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