Abstract
PurposeKetamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated.MethodsHuman iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy.ResultsTwenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P < 0.01), 14% increase in ROS production (P < 0.01), and 81% reduction in mitochondrial membrane potential (P < 0.01), compared with untreated cells. Lower concentration of ketamine (100 μM) decreased the ATP level (22%, P < 0.01) and increased the NADH/NAD+ ratio (46%, P < 0.05) without caspase activation. Transmission electron microscopy showed enhanced mitochondrial fission and autophagocytosis at the 100 μM ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation.ConclusionsWe established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons.
Highlights
Ketamine is widely used in general anesthesia, perioperative sedation and analgesia
Twenty-four-hour exposure of induced pluripotent stem cells (iPSCs)-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P < 0.01), 14% increase in reactive oxygen species (ROS) production (P < 0.01), and 81% reduction in mitochondrial membrane potential (P < 0.01), compared with untreated cells
Transmission electron microscopy showed enhanced mitochondrial fission and autophagocytosis at the 100 μM ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation
Summary
Recent studies have shown the possibility of neurotoxicity of ketamine in rodents and nonhuman primate neonatal brains [1,2,3,4,5,6]. The mechanism underlying the neurotoxicity of ketamine has not been fully shown In this context, there are some advantages in using cell lines established from human tissues as experimental models to study the cellular responses to toxic agents and to overcome interspecies differences and ethical issues. Ketamine-induced neural apoptosis has been demonstrated in human embryonic stem cell (hESC)-derived neurons [7, 8] These are landmark studies that have shown the mechanism of toxicity of anesthetics in human neurons. Ethical issues regarding the use of human embryos remain problematic [9,10,11]
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