title: Relationship between ketamine-induced developmental neurotoxicity and NMDA receptor-mediated calcium influx in neural stem cell-derived neurons.
abstract: Ketamine, a noncompetitive NMDA receptor antagonist, is used as a general anesthetic and recent data suggest that general anesthetics can cause neuronal damage when exposure occurs during early brain development. To elucidate the underlying mechanisms associated with ketamine-induced neurotoxicity, stem cell-derived models, such as rodent neural stem cells harvested from rat fetuses and/or neural stem cells derived from human induced pluripotent stem cells (iPSC) can be utilized. Prolonged exposure of rodent neural stem cells to clinically-relevant concentrations of ketamine resulted in elevated NMDA receptor levels as indicated by NR1subunit over-expression in neurons. This was associated with enhanced damage in neurons. In contrast, the viability and proliferation rate of undifferentiated neural stem cells were not significantly affected after ketamine exposure. Calcium imaging data indicated that 50μM NMDA did not cause a significant influx of calcium in typical undifferentiated neural stem cells; however, it did produce an immediate elevation of intracellular free Ca2+[Ca2+]iin differentiated neurons derived from the same neural stem cells. This paper reviews the literature on this subject and previous findings suggest that prolonged exposure of developing neurons to ketamine produces an increase in NMDA receptor expression (compensatory up-regulation) which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to neuronal cell death likely due to elevated reactive oxygen species generation. The absence of functional NMDA receptors in cultured neural stem cells likely explains why clinically-relevant concentrations of ketamine did not affect undifferentiated neural stem cell viability.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: Cheng.wang@fda.hhs.gov.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Tucker A
authors.initials: TA
authors.lastname: Patterson
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.affiliation: Office of the Director, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: William
authors.initials: W
authors.lastname: Slikker
mesh_terms: D000778:Anesthetics, Dissociative / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D006801:Humans; D007649:Ketamine / Q000633:toxicity*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000503:physiopathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D000778:Anesthetics, Dissociative; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D002118:Calcium
keywords: Calcium imaging; Development; Ketamine; NMDA receptors; Neural stem cells; Neurotoxicity